Oxindole compounds carrying a CO-bound spiro substituent and use thereof for treating vasopressin-related diseases

ABSTRACT

The present invention relates to novel substituted oxindole derivatives of formula I 
                         
wherein the variables are as defined in the claims and the description. The invention further relates to pharmaceutical compositions comprising compounds I and their use for the treatment of vasopressin-related disorders.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This claims priority to U.S. Provisional Patent Application No.61/993,874, filed on May 15, 2014, the entire contents of which is fullyincorporated herein by reference.

The present invention relates to novel substituted oxindole derivatives,pharmaceutical compositions comprising them, and their use for thetreatment of vasopressin-related disorders.

Vasopressin is an endogenous hormone which exerts various effects onorgans and tissues. It is suspected that the vasopressin system isinvolved in various pathological states such as, for example, heartfailure and high blood pressure. At present, three receptors (V1a, V1bor V3, and V2) via which vasopressin mediates its numerous effects areknown. Antagonists of these receptors are therefore being investigatedas possible new therapeutic approaches for the treatment of diseases (M.Thibonnier, Exp. Opin. Invest. Drugs 1998, 7(5), 729-740; T. Ryckmans,Current Opinion in Drug Discovery & Development 13 (2010), 538-547; G.Decaux et al., Lancet 371 (2008), 1624-1632; R. Lemmens-Gruber, M.Kamyar, Cell. Mol. Life Sci. 63 (2006), 1766-1779).

1-(Het)Arylsulfonyl-1,3-dihydro-2H-indol-2-ones have previously beendescribed as ligands of vasopressin receptors, for example in WO2005/030755, WO 2006/005609, WO 2006/080574, WO 2008/080970, WO2008/080971, WO 2008/080972, WO 2008/080973, WO 2009/071687, WO2009/071689, WO 2009/071690, WO2009/071691, WO 2009/083559, WO2010/009775 or WO 2010/142739.

Besides the binding affinity for the vasopressin V1b receptor, furtherproperties may be advantageous for the treatment and/or prophylaxis ofvasopressin-related disorders, such as, for example:

1.) a selectivity for the vasopressin V1b receptor compared with thevasopressin V1a receptor, i.e. the quotient of the binding affinity forthe V1a receptor (Ki(V1a) (determined in the unit “nanomolar (nM)”) andthe binding affinity for the V1b receptor (Ki(V1b)) (determined in theunit “nanomolar (nM)”). A larger quotient Ki(V1a)/Ki(V1b) means agreater V1b selectivity;

2.) a selectivity for the vasopressin V1b receptor compared with thevasopressin V2 receptor, i.e. the quotient of the binding affinity forthe V2 receptor (Ki(V2) (determined in the unit “nanomolar (nM)”) andthe binding affinity for the V1b receptor (Ki(V1b)) (determined in theunit “nanomolar (nM)”). A larger quotient Ki(V2)/Ki(V1b) means a greaterV1b selectivity;

3.) a selectivity for the vasopressin V1b receptor compared with theoxytocin OT receptor, i.e. the quotient of the binding affinity for theOT receptor (Ki(OT) (determined in the unit “nanomolar (nM)”) and thebinding affinity for the V1b receptor (Ki(V1b)) (determined in the unit“nanomolar (nM)”). A larger quotient Ki(OT)/Ki(V1b) means a greater V1bselectivity;

4.) the metabolic stability, for example determined from the half-lives,measured in vitro, in liver microsomes from various species (e.g. rat orhuman);

5.) no or only low inhibition of cytochrome P450 (CYP) enzymes:cytochrome P450 (CYP) is the name for a superfamily of heme proteinshaving enzymatic activity (oxidase). They are also particularlyimportant for the degradation (metabolism) of foreign substances such asdrugs or xenobiotics in mammalian organisms. The principalrepresentatives of the types and subtypes of CYP in the human body are:CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g.grapefruit juice, cimetidine, erythromycin) are used at the same time asmedicinal substances which are degraded by this enzyme system and thuscompete for the same binding site on the enzyme, the degradation thereofmay be slowed down and thus effects and side effects of the administeredmedicinal substance may be undesirably enhanced;

6.) a suitable solubility in water (in mg/ml);

7.) suitable pharmacokinetics (time course of the concentration of thecompound of the invention in plasma or in tissue, for example brain).The pharmacokinetics can be described by the following parameters:half-life (in h), volume of distribution (in 1·kg-1), plasma clearance(in 1·h-1·kg-1), AUC (area under the curve, area under theconcentration-time curve, in ng·h·1-1), oral bioavailability (thedose-normalized ratio of AUC after oral administration and AUC afterintravenous administration), the so-called brain-plasma ratio (the ratioof AUC in brain tissue and AUC in plasma);

8.) no or only low blockade of the hERG channel: compounds which blockthe hERG channel may cause a prolongation of the QT interval and thuslead to serious disturbances of cardiac rhythm (for example so-called“torsade de pointes”). The potential of compounds to block the hERGchannel can be determined by means of the displacement assay withradiolabelled dofetilide which is described in the literature (G. J.Diaz et al., Journal of Pharmacological and Toxicological Methods, 50(2004), 187 199). A smaller IC50 in this dofetilide assay means agreater probability of potent hERG blockade. In addition, the blockadeof the hERG channel can be measured by electrophysiological experimentson cells which have been transfected with the hERG channel, by so-calledwhole-cell patch clamping (G. J. Diaz et al., Journal of Pharmacologicaland Toxicological Methods, 50 (2004), 187-199).

It was therefore an object of the present invention to provide compoundsfor the treatment or prophylaxis of various vasopressin-relateddiseases. The compounds were intended to have a high activity andselectivity, especially a high affinity and selectivity vis-á-vis thevasopressin V1b receptor. In addition, the substance of the inventionwas intended to have one or more of the aforementioned advantages 1.) to8.).

The object is achieved by compounds of the formula I

wherein

-   A is a ring selected from phenyl and 6-membered hetaryl containing 1    or 2 nitrogen atoms as ring members, where ring A carries one    substituent R⁶ and optionally one substituent R⁷;-   B is a ring selected from phenyl, pyridyl and quinolinyl, where ring    B may carry 1, 2 or 3 substituents R⁸;-   X¹ is NH, CH₂ or O;-   X² is N or CH;-   X³, X⁴, X⁵ and X⁶, independently of each other, are selected from    —CH₂—, —O—, —S(O)_(c)—, —NH—, —C(O)—, —CH₂CH₂—, —CH₂O—, —OCH₂—,    —S(O)_(c)CH₂—, —CH₂S(O)_(c)—, CH₂NH—, —NHCH₂—, —CH₂C(O)— and    —C(O)CH₂—;-   X⁷ is NH, CH₂ or O;-   R¹ is selected from cyano, halogen, C₁-C₃-alkyl, fluorinated    C₁-C₃-alkyl, C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl,    C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy;-   R² is selected from hydrogen, cyano, halogen, C₁-C₃-alkyl,    fluorinated C₁-C₃-alkyl, C₃-C₆-cycloalkyl, fluorinated    C₃-C₆-cycloalkyl, C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy;-   R³ and R⁴, independently of each other and independently of each    occurrence, are selected from hydroxyl, C₁-C₄-alkyl,    C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy    and NR⁹R¹⁰, and in case that R³ or R⁴ are bound to a carbon ring    atom, are additionally selected from halogen; or-    two non-geminal radicals R³ form together a group —(CH₂)_(k)—,    where k is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group    may be replaced by a methyl group; or-    two non-geminal radicals R⁴ form together a group —(CH₂)_(k)—,    where k is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group    may be replaced by a methyl group; or-    two geminal radicals R³ form together a group —(CH₂)_(j)—, where j    is 2, 3, 4 or 5, where 1 or 2 hydrogen atoms in this group may be    replaced by a methyl group; or-    two geminal radicals R⁴ form together a group —(CH₂)_(j)—, where j    is 2, 3, 4 or 5, where 1 or 2 hydrogen atoms in this group may be    replaced by a methyl group; with the proviso that R³ and R⁴ are not    halogen, hydroxyl, C₁-C₄-alkoxy or C₁-C₄-haloalkoxy if they are    bound to a carbon atom in α-position to a nitrogen ring atom;-   R⁵ is selected from hydrogen, cyano, C₁-C₆-alkyl, C₂-C₆-alkenyl,    C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, where the four last-mentioned    radicals may be partially or fully halogenated and/or may carry one    or more substituents R¹¹; phenyl which may carry 1, 2 or 3    substituents R¹²; a 3-, 4-, 5-, 6- or 7-membered saturated,    partially unsaturated or maximally unsaturated heteromonocyclic ring    containing 1, 2 or 3 heteroatoms or heteroatom groups selected from    O, N, S, NO, SO and SO₂ as ring members; a 5-, 6-, 7-, 8-, 9-, 10-    or 11-membered saturated, partially unsaturated or maximally    unsaturated heterobicyclic ring containing 1, 2 or 3 heteroatoms or    heteroatom groups selected from O, N, S, NO, SO and SO₂ as ring    members, where the heteromonocyclic or heterobicyclic ring may carry    1, 2 or 3 substituents R¹²; —OR¹³; —S(O)₁R¹³; NR¹⁴R¹⁵; and    —C(═O)R¹⁶;-   R⁶ and R⁷, independently of each other, are selected from halogen,    cyano, hydroxyl, C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl,    C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy;-   each R⁸ is independently selected from halogen, cyano, hydroxyl,    C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl,    C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy;-   R⁹ and R¹⁰, independently of each other, are selected from hydrogen,    C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,    C₃-C₆-cycloalkyl-C₁-C₄-alkyl, phenyl and benzyl;-   each R¹¹ is independently selected from cyano, —OR¹³, —S(O)₁R¹³,    NR¹⁴R¹⁵, —C(═O)R¹⁶, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, phenyl    which may carry 1, 2 or 3 substituents R¹²; a 3-, 4-, 5-, 6- or    7-membered saturated, partially unsaturated or maximally unsaturated    heteromonocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom    groups selected from O, N, S, NO, SO and SO₂ as ring members, and a    5-, 6-, 7-, 8-, 9-, 10- or 11-membered saturated, partially    unsaturated or maximally unsaturated heterobicyclic ring containing    1, 2 or 3 heteroatoms or heteroatom groups selected from O, N, S,    NO, SO and SO₂ as ring members, where the heteromonocyclic or    heterobicyclic ring may carry 1, 2 or 3 substituents R¹²; and-    as a substituent on a cycloalkyl ring, R¹¹ is additionally selected    from C₁-C₄-alkyl and C₁-C₄-haloalkyl;-   each R¹² is independently selected from halogen, hydroxyl, cyano,    nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,    C₃-C₆-halocycloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,    C₁-C₄-alkylthio, C₁-C₄-haloalkylthio, C₁-C₄-alkylsulfinyl,    C₁-C₄-haloalkylsulfinyl, C₁-C₄-alkylsulfonyl,    C₁-C₄-haloalkylsulfonyl, phenyl, phenoxy, benzyloxy, where the    phenyl moiety in the three last-mentioned radicals may carry 1, 2 or    3 substituents selected from halogen, hydroxyl, cyano, C₁-C₄-alkyl,    C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy; and a 3-, 4-,    5-, 6- or 7-membered saturated, partially unsaturated or maximally    unsaturated heteromonocyclic ring containing 1, 2 or 3 heteroatoms    or heteroatom groups selected from O, N, S, NO, SO and SO₂ as ring    members, where the heteromonocyclic ring may carry 1, 2 or 3    substituents selected from halogen, hydroxyl, cyano, C₁-C₄-alkyl,    C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy;-   each R¹³ is independently selected from hydrogen, C₁-C₄-alkyl,    C₁-C₄-haloalkyl, C₁-C₄-alkyl which carries one substituent R¹⁷,    C₂-C₄-alkenyl, C₂-C₄-haloalkenyl, C₂-C₄-alkynyl, C₂-C₄-haloalkynyl,    C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, phenyl which may carry 1, 2    or 3 substituents selected from halogen, hydroxyl, cyano,    C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy; and    a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or    maximally unsaturated heterocyclic ring containing 1, 2 or 3    heteroatoms or heteroatom groups selected from O, N, S, NO, SO and    SO₂ as ring members, where the heterocyclic ring may carry 1, 2 or 3    substituents selected from halogen, hydroxyl, cyano, C₁-C₄-alkyl,    C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy;-   R¹⁴ and R¹⁵, independently of each other and independently of each    occurrence, are selected from hydrogen, C₁-C₄-alkyl,    C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, phenyl    which may carry 1, 2 or 3 substituents selected from halogen,    hydroxyl, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and    C₁-C₄-haloalkoxy; a 3-, 4-, 5-, 6- or 7-membered saturated,    partially unsaturated or maximally unsaturated heterocyclic ring    containing 1, 2 or 3 heteroatoms or heteroatom groups selected from    O, N, S, NO, SO and SO₂ as ring members, where the heterocyclic ring    may carry 1, 2 or 3 substituents selected from halogen, hydroxyl,    cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and    C₁-C₄-haloalkoxy; C₁-C₄-alkylcarbonyl and C₁-C₄-haloalkylcarbonyl;-   each R¹⁶ is independently selected from hydrogen, C₁-C₄-alkyl,    C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, phenyl,    —OR¹³ and NR¹⁴R¹⁵;-   each R¹⁷ is independently selected from cyano, hydroxyl,    C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio,    C₁-C₄-haloalkylthio, C₁-C₄-alkylsulfinyl, C₁-C₄-haloalkylsulfinyl,    C₁-C₄-alkylsulfonyl, C₁-C₄-haloalkylsulfonyl, NR¹⁴R¹⁵;    C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₃-C₆-cycloalkyl,    C₃-C₆-halocycloalkyl, phenyl which may carry 1, 2 or 3 substituents    R¹²; a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated    or maximally unsaturated heteromonocyclic ring containing 1, 2 or 3    heteroatoms or heteroatom groups selected from O, N, S, NO, SO and    SO₂ as ring members, and a 5-, 6-, 7-, 8-, 9-, 10- or 11-membered    saturated, partially unsaturated or maximally unsaturated    heterobicyclic ring containing 1, 2 or 3 heteroatoms or heteroatom    groups selected from O, N, S, NO, SO and SO₂ as ring members, where    the heteromonocyclic or heterobicyclic ring may carry 1, 2 or 3    substituents R¹²;-   a is 0, 1 or 2;-   b is 0, 1 or 2;-   c is 0, 1 or 2; and-   l is 0, 1 or 2;    and the N-oxides, stereoisomers and pharmaceutically acceptable    salts thereof, and the compound of the formula I, wherein at least    one of the atoms has been replaced by its stable, non-radioactive    isotope.

Accordingly, the present invention relates to compounds of the formula I(also “compounds I” hereinafter) and the N-oxides, stereoisomers and thepharmaceutically acceptable salts of the compounds I.

In another aspect, the invention relates to a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof formula I or an N-oxide, a stereoisomer or a pharmaceuticallyacceptable salt thereof, or comprising at least one compound as definedabove or below wherein at least one of the atoms has been replaced byits stable, non-radioactive isotope, preferably wherein at least onehydrogen atom has been replaced by a deuterium atom, in combination withat least one pharmaceutically acceptable carrier and/or auxiliarysubstance.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a stereoisomer or a pharmaceutically acceptable saltthereof for use as a medicament.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a stereoisomer or a pharmaceutically acceptable saltthereof for the treatment and/or prophylaxis of vasopressin-relateddiseases, especially of disorders which respond to the modulation of thevasopressin receptor, in particular of the V1b receptor.

In yet another aspect, the invention relates to the use of a compound offormula I or of an N-oxide, a stereoisomer or a pharmaceuticallyacceptable salt thereof for the manufacture of a medicament for thetreatment and/or prophylaxis of vasopressin-related diseases; especiallyof disorders which respond to the modulation of the vasopressinreceptor, in particular of the V1b receptor.

The pharmaceutically acceptable salts of compounds of the formula I,which are also referred to as physiologically tolerated salts, areordinarily obtainable by reacting the free base of the compounds I ofthe invention (i.e. of the compounds I according to structural formulaI) with suitable acids. Examples of suitable acids are listed in“Fortschritte der Arzneimittelforschung”, 1966, Birkhäauser Verlag, vol.10, pp. 224-285. These include for example hydrochloric acid, citricacid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid,acetic acid, trifluoroacetic acid, formic acid, maleic acid and fumaricacid.

The term “stereoisomers” encompasses both optical isomers, such asenantiomers or diastereomers, the latter existing due to more than onecenter of chirality in the molecule, as well as geometrical isomers(cis/trans isomers; correctly speaking, these are also diastereomers).The term “stereoisomers” also encompasses conformers (to be more preciseconfiguration isomers) which are caused by the hindered or deceleratedinversion at one or more nitrogen atoms, especially ring nitrogen atoms,such as X⁷ (if this is N, of course); like the isomers described by Y.Naruse et al. in Tetrahedron Asymmetry 2013, 24, 169-171.

Depending on the substitution pattern, the compounds of the formula Imay have one or more centers of chirality, in which case they arepresent as mixtures of enantiomers or diastereomers. One center ofchirality is the carbon ring atom in the 3-position of the oxindolescaffold (the carbon atom which carries the group X¹—C(O)-spiro ringsand ring A). The compounds of the formula I may further have axialchirality due to the spiro system. The invention provides both the pureenantiomers or diastereomers and their mixtures and the use according tothe invention of the pure enantiomers or diastereomers of the compound Ior its mixtures. Suitable compounds of the formula I also include allpossible geometrical stereoisomers (cis/trans isomers) and mixturesthereof.

Halogen in the terms of the present invention is fluorine, chlorine,bromine or iodine, preferably fluorine, chlorine or bromine andespecially fluorine or chlorine.

C₁-C₃-Alkyl is a linear or branched alkyl radical having 1 to 3 carbonatoms, such as methyl, ethyl, n-propyl or isopropyl. C₁-C₄-Alkyl is alinear or branched alkyl radical having 1 to 4 carbon atoms, such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl ortert-butyl. C₁-C₆-Alkyl is a linear or branched alkyl radical having 1to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-tri-methylpropyl, 1-ethyl-1-methylpropyl, or1-ethyl-2-methylpropyl.

Fluorinated alkyl is a straight-chain or branched alkyl group havingfrom 1 to 4 (=fluorinated C₁-C₄-alkyl), in particular 1 to 3 carbonatoms (=fluorinated C₁-C₃-alkyl), more preferably 1 or 2 carbon atoms(=fluorinated C₁-C₂-alkyl), wherein at least one, e.g. 1, 2, 3, 4 or allof the hydrogen atoms are replaced by fluorine atoms. Examples forfluorinated C₁-C₂-alkyl are fluoromethyl, difluoromethyl,trifluoromethyl, 1-fluoroethyl, (R)-1-fluoroethyl, (S)-1-fluoroethyl,2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, pentafluoroethyl and the like. Examples forfluorinated C₁-C₃-alkyl are, apart those mentioned above for fluorinatedC₁-C₂-alkyl, 1-fluoropropyl, (R)-1-fluoropropyl, (S)-1-fluoropropyl,2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl,3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-fluoropropyl,2-fluoro-1-methylethyl, (R)-2-fluoro-1-methylethyl,(S)-2-fluoro-1-methylethyl, 2,2-difluoro-1-methylethyl,(R)-2,2-difluoro-1-methylethyl, (S)-2,2-difluoro-1-methylethyl,1,2-difluoro-1-methylethyl, (R)-1,2-difluoro-1-methylethyl,(S)-1,2-difluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl,(R)-2,2,2-trifluoro-1-methylethyl, (S)-2,2,2-trifluoro-1-methylethyl,2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl andthe like. Examples for fluorinated C₁-C₄-alkyl are, apart thosementioned above for fluorinated C₁-C₃-alkyl, 1-fluorobutyl,(R)-1-fluorobutyl, (S)-1-fluorobutyl, 2-fluorobutyl, 3-fluorobutyl,4-fluorobutyl, 1,1-difluorobutyl, 2,2-difluorobutyl, 3,3-difluorobutyl,4,4-difluorobutyl, 4,4,4-trifluorobutyl, and the like.

Haloalkyl, which is also expressed as “alkyl which is partially or fullyhalogenated”, is a straight-chain or branched alkyl group having from 1to 6 (═C₁-C₆-haloalkyl), in particular 1 to 4 carbon atoms(═C₁-C₄-haloalkyl), wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by a halogen atom. Examples forC₁-C₄-haloalkyl are, apart those mentioned above for fluorinatedC₁-C₄-alkyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl,chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl,1-chloroethyl, 1-bromoethyl, 2-chloro-2-fluoroethyl,2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,2,2,2-trichloroethyl, 3-chloropropyl, 4-chlorobutyl and the like.Examples for C₁-C₆-haloalkyl are, apart from those listed forC₁-C₄-haloalkyl, 1-fluoropentyl, 1-chloropenthyl, 1-bromopentyl,1-fluorohexyl, 1-chlorohexy, 1-bromohexyl and the like.

C₁-C₃-Hydroxyalkyl is C₁-C₃-alkyl as defined above wherein one of thehydrogen atoms is replaced by a hydroxyl group. Examples arehydroxymethyl, 1- and 2-hydroxyethyl, 1-, 2- and 3-hydroxy-n-propyl,1-(hydroxymethyl)-ethyl and the like.

The term “alkenyl” as used herein refers to monounsaturatedstraight-chain or branched hydrocarbon radicals having 2 to 3(“C₂-C₃-alkenyl”), 2 to 4 (“C₂-C₄-alkenyl”) or 2 to 6 (“C₂-C₆-alkenyl”)carbon atoms and a double bond in any position. Examples forC₂-C₃-alkenyl are ethenyl, 1-propenyl, 2-propenyl or 1-methylethenyl.Examples for C₂-C₄-alkenyl are ethenyl, 1-propenyl, 2-propenyl,1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl.Examples for C₂-C₆-alkenyl are ethenyl, 1-propenyl, 2-propenyl,1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl,2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl,2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl,3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl,1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl,1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl,2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl,3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl,1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl,1-ethyl-2-methyl-2-propenyl and the like.

The term “haloalkenyl” as used herein, which is also expressed as“alkenyl which is partially or fully halogenated”, refers to unsaturatedstraight-chain or branched hydrocarbon radicals having 2 to 3(“C₂-C₃-haloalkenyl”), 2 to 4 (“C₂-C₄-haloalkenyl”) or 2 to 6(“C₂-C₆-haloalkenyl”) carbon atoms and a double bond in any position (asmentioned above), where some or all of the hydrogen atoms in thesegroups are replaced by halogen atoms as mentioned above, in particularfluorine, chlorine and bromine, for example chlorovinyl, chloroallyl andthe like.

The term “alkynyl” as used herein refers to straight-chain or branchedhydrocarbon groups having 2 to 3 (“C₂-C₃-alkynyl”), 2 to 4(“C₂-C₄-alkynyl”) or 2 to 6 (“C₂-C₆-alkynyl”) carbon atoms and one ortwo triple bonds in any position. Examples for C₂-C₃-alkynyl areethynyl, 1-propynyl or 2-propynyl. Examples for C₂-C₄-alkynyl areethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl and the like. Examples for C₂-C₆-alkynyl areethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl,3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl,2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl,3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl,1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl,1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl andthe like.

The term “haloalkynyl” as used herein, which is also expressed as“alkynyl which is partially or fully halogenated”, refers to unsaturatedstraight-chain or branched hydrocarbon radicals having 2 to 3(“C₂-C₃-haloalkynyl”), 2 to 4 (“C₂-C₄-haloalkynyl”) or 2 to 6(“C₂-C₆-haloalkynyl”) carbon atoms and one or two triple bonds in anyposition (as mentioned above), where some or all of the hydrogen atomsin these groups are replaced by halogen atoms as mentioned above, inparticular fluorine, chlorine and bromine.

C₃-C₇-Cycloalkyl is a monocyclic saturated hydrocarbon radical having 3to 7, in particular 3 to 6 (“C₃-C₆-cycloalkyl”) or 3 to 5(“C₃-C₅-cycloalkyl”) or 3 to 4 (“C₃-C₄-cycloalkyl”) carbon atoms.Examples of C₃-C₄-cycloalkyl comprise cyclopropyl and cyclobutyl.Examples of C₃-C₅-cycloalkyl comprise cyclopropyl, cyclobutyl andcyclopentyl. Examples of C₃-C₆-cycloalkyl comprise cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. Examples of C₃-C₇-cycloalkylcomprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

Fluorinated C₃-C₇-cycloalkyl is a monocyclic saturated hydrocarbonradical having 3 to 7, in particular 3 to 6 (“fluorinatedC₃-C₆-cycloalkyl”) or 3 to 5 (“fluorinated C₃-C₅-cycloalkyl”) or 3 to 4(“fluorinated C₃-C₄-cycloalkyl”) carbon ring members (as mentionedabove) in which some or all of the hydrogen atoms are replaced byfluorine atoms. Examples for fluorinated C₃-C₄-cycloalkyl are1-fluorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl,1-fluorocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl,2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl and the like. Examplesfor fluorinated C₃-C₅-cycloalkyl are additionally 1-fluorocyclopentyl,2-fluorocyclopentyl, 3-fluorocyclopentyl, 2,2-difluorocyclopentyl,3,3-difluorocyclopentyl, and the like. Examples for fluorinatedC₃-C₆-cycloalkyl are additionally 1-fluorocyclohexyl,2-fluorocyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl,2,2-difluorocyclohexyl, 3,3-difluorocyclohexyl, 4,4-difluorocyclohexyl,and the like. Examples for fluorinated C₃-C₇-cycloalkyl are additionally1-fluorocycloheptyl, 2-fluorocycloheptyl, 3-fluorocycloheptyl,4-fluorocycloheptyl, 2,2-difluorocycloheptyl, 3,3-difluorocycloheptyl,4,4-difluorocycloheptyl, and the like.

C₃-C₇-Halocycloalkyl is a monocyclic saturated hydrocarbon radicalhaving 3 to 7, in particular 3 to 6 (“C₃-C₆-halocycloalkyl”) or 3 to 5(“C₃-C₅-halocycloalkyl”) or 3 to 4 (“C₃-C₄-halocycloalkyl”) carbon ringmembers (as mentioned above) in which some or all of the hydrogen atomsare replaced by halogen atoms as mentioned above, in particularfluorine, chlorine and bromine.

The term “C₃-C₆-cycloalkyl-C₁-C₄-alkyl” which is bound to the remainderof the molecule via a C₁-C₄-alkyl group, as defined above. Examples forC₃-C₆-cycloalkyl-C₁-C₄-alkyl are cyclopropylmethyl,1-cyclopropyl-1-ethyl, 1-cyclopropyl-2-ethyl, 1-cyclopropyl-1-propyl,1-cyclopropyl-2-propyl, 2-cyclopropyl-1-propyl, 2-cyclopropyl-2-propyl,1-cyclopropyl-3-propyl, cyclobutylmethyl, 1-cyclobutyl-1-ethyl,1-cyclobutyl-2-ethyl, 1-cyclobutyl-1-propyl, 1-cyclobutyl-2-propyl,2-cyclobutyl-1-propyl, 2-cyclobutyl-2-propyl, 1-cyclobutyl-3-propyl,cyclopentylmethyl, 1-cyclopentyl-1-ethyl, 1-cyclopentyl-2-ethyl,1-cyclopentyl-1-propyl, 1-cyclopentyl-2-propyl, 2-cyclopentyl-1-propyl,2-cyclopentyl-2-propyl, 1-cyclopentyl-3-propyl, cyclohexylmethyl,1-cyclohexyl-1-ethyl, 1-cyclohexyl-2-ethyl, 1-cyclohexyl-1-propyl,1-cyclohexyl-2-propyl, 2-cyclohexyl-1-propyl, 2-cyclohexyl-2-propyl and1-cyclohexyl-3-propyl.

C₃-C₆-Cycloalkylmethyl is for example cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

C₁-C₃-Alkoxy is a linear or branched alkyl radical linked via an oxygenatom and having 1 to 3 carbon atoms. Examples are methoxy, ethoxy,n-propoxy and isopropoxy. C₁-C₄-Alkoxy is a linear or branched alkylradical linked via an oxygen atom and having 1 to 4 carbon atoms.Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,sec-butoxy, isobutoxy and tert-butoxy.

C₁-C₄-Haloalkoxy is C₁-C₄-alkoxy as defined above wherein at least one,e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a halogenatom. Preferably, C₁-C₄-haloalkoxy is fluorinated C₁-C₄-alkoxy. This isa straight-chain or branched alkoxy group having from 1 to 4, inparticular 1 to 3 carbon atoms (=fluorinated C₁-C₃-alkoxy), morepreferably 1 or 2 carbon atoms (=fluorinated C₁-C₂-alkoxy), wherein atleast one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced byfluorine atoms, such as in fluoromethoxy, difluoromethoxy,trifluoromethoxy, 1-fluoroethoxy, (R)-1-fluoroethoxy,(S)-1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy,2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoropropoxy,(R)-1-fluoropropoxy, (S)-1-fluoropropoxy, 2-fluoropropoxy,3-fluoropropoxy, 1,1-difluoropropoxy, 2,2-difluoropropoxy,3,3-difluoropropoxy, 3,3,3-trifluoropropoxy, 2-fluoro-1-methylethoxy,(R)-2-fluoro-1-methylethoxy, (S)-2-fluoro-1-methylethoxy,2,2-difluoro-1-methylethoxy, (R)-2,2-difluoro-1-methylethoxy,(S)-2,2-difluoro-1-methylethoxy, 1,2-difluoro-1-methylethoxy,(R)-1,2-difluoro-1-methylethoxy, (S)-1,2-difluoro-1-methylethoxy,2,2,2-trifluoro-1-methylethoxy, (R)-2,2,2-trifluoro-1-methylethoxy,(S)-2,2,2-trifluoro-1-methylethoxy, 2-fluoro-1-(fluoromethyl)ethoxy,1-(difluoromethyl)-2,2-difluoroethoxy, (R)-1-fluorobutoxy,(S)-1-fluorobutoxy, 2-fluorobutoxy, 3-fluorobutoxy, 4-fluorobutoxy,1,1-difluorobutoxy, 2,2-difluorobutoxy, 3,3-difluorobutoxy,4,4-difluorobutoxy, 4,4,4-trifluorobutoxy, etc.

C₁-C₄-Alkylthio is a C₁-C₄-alkyl group, as defined above, attached via asulfur atom. Examples are methylthio, ethylthio, n-propylthio,1-methylethylthio (isopropylthio), butylthio, 1-methylpropylthio(sec-butylthio), 2-methylpropylthio (isobutylthio) or1,1-dimethylethylthio (tert-butylthio).

C₁-C₄-Haloalkylthio is a C₁-C₄-haloalkyl group, as defined above,attached via a sulfur atom. Examples are SCH₂F, SCHF₂, SCF₃, SCH₂Cl,SCHCl₂, SCCl₃, chlorofluoromethylthio, dichlorofluoromethylthio,chlorodifluoromethylthio, 2-fluoroethylthio, 2-chloroethylthio,2-bromoethylthio, 2-iodoethylthio, 2,2-difluoroethylthio,2,2,2-trifluoroethylthio, 2-chloro-2-fluoroethylthio,2-chloro-2,2-difluoroethylthio, 2,2-dichloro-2-fluoroethylthio,2,2,2-trichloroethylthio, SC₂F₅, 2-fluoropropylthio, 3-fluoropropylthio,2,2-difluoropropylthio, 2,3-difluoropropylthio, 2-chloropropylthio,3-chloropropylthio, 2,3-dichloropropylthio, 2-bromopropylthio,3-bromopropylthio, 3,3,3-trifluoropropylthio, 3,3,3-trichloropropylthio,SCH₂—C₂F₅, SCF₂—C₂F₅, 1-(CH₂F)-2-fluoroethylthio,1-(CH₂Cl)-2-chloroethylthio, 1-(CH₂Br)-2-bromoethylthio,4-fluorobutylthio, 4-chlorobutylthio, 4-bromobutylthio ornonafluorobutylthio.

C₁-C₄-Alkylsulfinyl is a C₁-C₄-alkyl group, as defined above, attachedvia a sulfinyl [S(O)]group. Examples are methylsulfinyl, ethylsulfinyl,n-propylsulfinyl, 1-methylethylsulfinyl (isopropylsulfinyl),butylsulfinyl, 1-methylpropylsulfinyl (sec-butylsulfinyl),2-methylpropylsulfinyl (isobutylsulfinyl) or 1,1-dimethylethylsulfinyl(tert-butylsulfinyl).

C₁-C₄-Haloalkylsulfinyl is a C₁-C₄-haloalkyl group, as defined above,attached via a sulfinyl [S(O)]group. Examples are S(O)CH₂F, S(O)CHF₂,S(O)CF₃, S(O)CH₂Cl, S(O)CHCl₂, S(O)CCl₃, chlorofluoromethylsulfinyl,dichlorofluoromethylsulfinyl, chlorodifluoromethylsulfinyl,2-fluoroethylsulfinyl, 2-chloroethylsulfinyl, 2-bromoethylsulfinyl,2-iodoethylsulfinyl, 2,2-difluoroethylsulfinyl,2,2,2-trifluoroethylsulfinyl, 2-chloro-2-fluoroethylsulfinyl,2-chloro-2,2-difluoroethylsulfinyl, 2,2-dichloro-2-fluoroethylsulfinyl,2,2,2-trichloroethylsulfinyl, S(O)C₂F₅, 2-fluoropropylsulfinyl,3-fluoropropylsulfinyl, 2,2-difluoropropylsulfinyl,2,3-difluoropropylsulfinyl, 2-chloropropylsulfinyl,3-chloropropylsulfinyl, 2,3-dichloropropylsulfinyl,2-bromopropylsulfinyl, 3-bromopropylsulfinyl,3,3,3-trifluoropropylsulfinyl, 3,3,3-trichloropropylsulfinyl,S(O)CH₂—C₂F₅, S(O)CF₂—C₂F₅, 1-(CH₂F)-2-fluoroethylsulfinyl,1-(CH₂Cl)-2-chloroethylsulfinyl, 1-(CH₂Br)-2-bromoethylsulfinyl,4-fluorobutylsulfinyl, 4-chlorobutylsulfinyl, 4-bromobutylsulfinyl ornonafluorobutylsulfinyl.

C₁-C₄-Alkylsulfonyl is a C₁-C₄-alkyl group, as defined above, attachedvia a sulfonyl [S(O)₂]group. Examples are methylsulfonyl, ethylsulfonyl,n-propylsulfonyl, 1-methylethylsulfonyl (isopropylsulfonyl),butylsulfonyl, 1-methylpropylsulfonyl (sec-butylsulfonyl),2-methylpropylsulfonyl (isobutylsulfonyl) or 1,1-dimethylethylsulfonyl(tert-butylsulfonyl).

C₁-C₄-Haloalkylsulfonyl is a C₁-C₄-haloalkyl group, as defined above,attached via a sulfonyl [S(O)₂]group. Examples are S(O)₂CH₂F, S(O)₂CHF₂,S(O)₂CF₃, S(O)₂CH₂Cl, S(O)₂CHCl₂, S(O)₂CCl₃, chlorofluoromethylsulfonyl,dichlorofluoromethylsulfonyl, chlorodifluoromethylsulfonyl,2-fluoroethylsulfonyl, 2-chloroethylsulfonyl, 2-bromoethylsulfonyl,2-iodoethylsulfonyl, 2,2-difluoroethylsulfonyl,2,2,2-trifluoroethylsulfonyl, 2-chloro-2-fluoroethylsulfonyl,2-chloro-2,2-difluoroethylsulfonyl, 2,2-dichloro-2-fluoroethylsulfonyl,2,2,2-trichloroethylsulfonyl, S(O)₂C₂F₅, 2-fluoropropylsulfonyl,3-fluoropropylsulfonyl, 2,2-difluoropropylsulfonyl,2,3-difluoropropylsulfonyl, 2-chloropropylsulfonyl,3-chloropropylsulfonyl, 2,3-dichloropropylsulfonyl,2-bromopropylsulfonyl, 3-bromopropylsulfonyl,3,3,3-trifluoropropylsulfonyl, 3,3,3-trichloropropylsulfonyl,S(O)₂CH₂—C₂F₅, S(O)₂CF₂—C₂F₅, 1-(CH₂F)-2-fluoroethylsulfonyl,1-(CH₂Cl)-2-chloroethylsulfonyl, 1-(CH₂Br)-2-bromoethylsulfonyl,4-fluorobutylsulfonyl, 4-chlorobutylsulfonyl, 4-bromobutylsulfonyl ornonafluorobutylsulfonyl.

C₁-C₄-Alkylcarbonyl is a C₁-C₄-alkyl group, as defined above, attachedvia a carbonyl [C(═O)]group. Examples are acetyl (methylcarbonyl),propionyl (ethylcarbonyl), propylcarbonyl, isopropylcarbonyl,n-butylcarbonyl and the like.

C₁-C₄-Haloalkylcarbonyl is a C₁-C₄-haloalkyl group, as defined above,attached via a carbonyl [C(═O)]group. Examples aretrifluoromethylcarbonyl, 2,2,2-trifluoroethylcarbonyl and the like.

Examples for “6-membered hetaryl containing 1 or 2 nitrogen atoms asring members” are pyridyl, such as pyridin-2-yl, pyridin-3-yl orpyridin-4-yl, pyridazinyl, such as pyridazin-3-yl or pyridazin-4-yl,pyrimidinyl, such as pyrimidin-2-yl, pyrimidin-4-yl or pyrimidin-5-yl,and pyrazinyl.

The term “3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturatedor maximally unsaturated heterocyclic ring containing 1, 2 or 3heteroatoms or heteroatom groups selected from O, N, S, NO, SO and SO₂as ring members” denotes a 3-, 4-, 5-, 6- or 7-membered saturated,partially unsaturated or maximum unsaturated heteromonocyclic ringcontaining 1, 2 or 3 heteroatoms or heteroatom groups selected from O,N, S, NO, SO and SO₂, as ring members.

Unsaturated rings contain at least one C—C and/or C—N and/or N—N doublebond(s). Maximally unsaturated rings contain as many conjugated C—Cand/or C—N and/or N—N double bonds as allowed by the ring size.Maximally unsaturated 5- or 6-membered heterocyclic rings are aromatic.Partially unsaturated rings contain less C—C and/or C—N and/or N—Ndouble bonds than allowed by the ring size. The heterocyclic ring may beattached to the remainder of the molecule via a carbon ring member orvia a nitrogen ring member. As a matter of course, the heterocyclic ringcontains at least one carbon ring atom. If the ring contains more thanone O ring atom, these are not adjacent.

The term “3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturatedor maximum unsaturated heterocyclic ring containing 1, 2 or 3heteroatoms or heteroatom groups selected from O, N, S, NO, SO and SO₂,as ring members” [wherein “maximum unsaturated” includes also“aromatic”] as used herein denotes monocyclic radicals, the monocyclicradicals being saturated, partially unsaturated or maximum unsaturated(including aromatic). 7-membered rings cannot be aromatic; they arehomoaromatic if maximally unsaturated (3 double bonds).

Examples of a 3-, 4-, 5-, 6- or 7-membered saturated heterocyclic ringinclude: Oxiranyl, thiiranyl, aziridinyl, oxetanyl, thietanyl,azetidinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydrothien-2-yl, tetrahydrothien-3-yl, pyrrolidin-1-yl,pyrrolidin-2-yl, pyrrolidin-3-yl, pyrazolidin-1-yl, pyrazolidin-3-yl,pyrazolidin-4-yl, pyrazolidin-5-yl, imidazolidin-1-yl,imidazolidin-2-yl, imidazolidin-4-yl, oxazolidin-2-yl, oxazolidin-3-yl,oxazolidin-4-yl, oxazolidin-5-yl, isoxazolidin-2-yl, isoxazolidin-3-yl,isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolidin-2-yl,thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl,isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl,isothiazolidin-5-yl, 1,2,4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin-5-yl,1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl,1,2,4-triazolidin-3-yl, 1,3,4-oxadiazolidin-2-yl,1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-1-yl,1,3,4-triazolidin-2-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl,1,3-dioxan-5-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl,piperidin-3-yl, piperidin-4-yl, hexahydropyridazin-3-yl,hexahydropyridazin-4-yl, hexahydropyrimidin-2-yl,hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, piperazin-1-yl,piperazin-2-yl, 1,3,5-hexahydrotriazin-1-yl, 1,3,5-hexahydrotriazin-2-yland 1,2,4-hexahydrotriazin-3-yl, morpholin-2-yl, morpholin-3-yl,morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl,thiomorpholin-4-yl, 1-oxothiomorpholin-2-yl, 1-oxothiomorpholin-3-yl,1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-2-yl,1,1-dioxothiomorpholin-3-yl, 1,1-dioxothiomorpholin-4-yl, azepan-1-,-2-, -3- or -4-yl, oxepan 2-, -3-, -4- or -5-yl,hexahydro-1,3-diazepinyl, hexahydro-1,4-diazepinyl,hexahydro-1,3-oxazepinyl, hexahydro-1,4-oxazepinyl,hexahydro-1,3-dioxepinyl, hexahydro-1,4-dioxepinyl and the like.

Examples of a 3-, 4-, 5-, 6- or 7-membered partially unsaturatedheterocyclic ring include: 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl,2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl,2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl,2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl,2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl,2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl,2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl,2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl,2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl,2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl,2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl,2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl,2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl,3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl,3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl,4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl,4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl,2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl,3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl,3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl,2-, 3-, 4-, 5- or 6-di- or tetrahydropyridinyl, 3-di- ortetrahydropyridazinyl, 4-di- or tetrahydropyridazinyl, 2-di- ortetrahydropyrimidinyl, 4-di- or tetrahydropyrimidinyl, 5-di- ortetrahydropyrimidinyl, di- or tetrahydropyrazinyl, 1,3,5-di- ortetrahydrotriazin-2-yl, 1,2,4-di- or tetrahydrotriazin-3-yl,2,3,4,5-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,3,4,5,6-tetrahydro[2H]azepin-2-, -3-, -4-, -5-, -6- or -7-yl,2,3,4,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,2,3,6,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,tetrahydrooxepinyl, such as 2,3,4,5-tetrahydro[1H]oxepin-2-, -3-, -4-,-5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6-or -7-yl, 2,3,6,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl,tetrahydro-1,3-diazepinyl, tetrahydro-1,4-diazepinyl,tetrahydro-1,3-oxazepinyl, tetrahydro-1,4-oxazepinyl,tetrahydro-1,3-dioxepinyl and tetrahydro-1,4-dioxepinyl.

Examples for a 3-, 4-, 5-, 6- or 7-membered maximally unsaturated(including aromatic) heterocyclic ring are 5- or 6-memberedheteroaromatic rings, such as 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 2-pyridinyl,3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl,1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl, and also homoaromaticradicals, such as 1H-azepine, 1H-[1,3]-diazepine and 1H-[1,4]-diazepine.

In the present invention, the “heterobicyclic rings” contain two ringswhich have at least one ring atom in common. At least one of the tworings contains a heteroatom or heteroatom group selected from N, O, S,NO, SO and SO₂ as ring member. The term comprises condensed (fused) ringsystems, in which the two rings have two neighboring ring atoms incommon, as well as spiro systems, in which the rings have only one ringatom in common, and bridged systems with at least three ring atoms incommon.

Examples for Fused Systems:

Examples for a 7-, 8-, 9- or 10-membered saturated heterobicyclic ringcontaining 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selectedfrom N, O, S, NO, SO and SO₂, as ring members are:

Examples for a 8-, 9- or 10-membered partially unsaturatedheterobicyclic ring containing 1, 2 or 3 (or 4) heteroatoms orheteroatom groups selected from N, O, S, NO, SO and SO₂, as ring membersare:

Examples for a 8-, 9- or 10-membered maximally unsaturatedheterobicyclic ring containing 1, 2 or 3 (or 4) heteroatoms orheteroatom groups selected from N, O, S, NO, SO and SO₂, as ring membersare:

Examples for spiro-bound 7-, 8-, 9- or 10-membered heterobicyclic ringscontaining 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selectedfrom N, O, S, NO, SO and SO₂, as ring members are

Examples for bridged 7-, 8-, 9- or 10-membered heterobicyclic ringscontaining 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selectedfrom N, O, S, NO, SO and SO₂, as ring members are

and the like.

In the above structures # denotes the attachment point to the remainderof the molecule. The attachment point is not restricted to the ring onwhich is shown, but can be on either of the fused rings, and may be on acarbon or on a nitrogen ring atom. If the rings carry one or moresubstituents, these may be bound to carbon and/or to nitrogen ringatoms.

The compounds of the invention of the formula I and their N-oxides,stereoisomers and pharmacologically acceptable salts may also be presentin the form of solvates or hydrates. Solvates mean in the context of thepresent invention crystalline forms of the compounds I or of theirpharmaceutically acceptable salts which comprise solvent moleculesincorporated in the crystal lattice. The solvent molecules arepreferably incorporated in stoichiometric ratios. Hydrates are aspecific form of solvates; the solvent in this case being water.

The statements made hereinafter concerning suitable and preferredfeatures of the invention, especially concerning the radicals A, B, X¹,X², X³, X⁴, X⁵, X⁶, X⁷, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, a, b, c, k, l, m, n, o and p in thecompound I, but also concerning the features of the process of theinvention and of the use according to the invention apply both taken ontheir own as well as preferably in any possible combination with oneanother.

The compounds I are preferably provided in the form of the free base(i.e. according to structural formula I) or in the form of their acidaddition salts.

As a matter of course, each radical R³, if present, replaces a hydrogenatom of the ring members X², X³ and/or X⁴, e.g. the hydrogen atom in X²if this is CH or the hydrogen atom(s) in the CH₂ or NH moieties of X³and/or X⁴.

Alike, each radical R⁴, if present, as well as the mandatory radical R⁵replace a hydrogen atom of the ring members X⁵, X⁶ and/or X⁷, e.g. thehydrogen atom(s) in the CH₂ or NH moieties of X⁵, X⁶ and/or X⁷.

R⁵ can be bound to any of the ring members X⁵, X⁶ and/or X⁷, but if X⁷is NH or CH₂, R⁵ is preferably bound to X⁷, where it replaces a hydrogenatom of this NH or CH₂ group X⁷ (so that X⁷ is NR⁵ or CHR⁵ or C(R⁴)R⁵).

If X³, X⁴, X⁵, X⁶ or X⁷ are NH, preferably they do not carry an N-boundradical R³, R⁴ or R⁵.

In a preferred embodiment, X¹ is NH or CH₂, and in particular NH.

In a preferred embodiment, X³, X⁴, X⁵ and X⁶, independently of eachother, are selected from —CH₂— and —CH₂CH₂—.

In a preferred embodiment, X⁷ is NH or CH₂, and in particular NH.

In a particular embodiment, if X² is CH, X¹ is simultaneously NH or O,especially NH.

A is preferably phenyl or pyridyl, in particular phenyl or 3-pyridyl,where A carries one substituent R⁶ and optionally one substituent R⁷.

In a preferred embodiment, A is phenyl or 3-pyridyl, and carries theradical R⁶ in the 2-position and the radical R⁷, if present, in the 4-or 5-position, relative to the 1-position of the attachment point of Ato the remainder of the molecule.

In particular, A is phenyl or 3-pyridyl, and carries the radical R⁶ inthe 2-position, relative to the 1-position of the attachment point of Ato the remainder of the molecule, and carries no radical R⁷.

B is preferably phenyl or 2-pyridyl, where B may carry 1, 2 or 3substituents R⁸.

In case that B is 2-pyridyl and carries one substituent R⁸, this ispreferably bound in the 4-position, relative to the 1-position of theattachment point of B to the remainder of the molecule (i.e. to thesulfonyl group).

In case that B is phenyl and carries one substituent R⁸, this ispreferably bound in the 2- or 4-position, relative to the 1-position ofthe attachment point of B to the remainder of the molecule (i.e. to thesulfonyl group).

In case that B is 2-pyridyl and carries two substituents R⁸, these arepreferably bound in the 4- and 5- or 4- and 6-positions, relative to the1-position of the attachment point of B to the remainder of the molecule(i.e. to the sulfonyl group).

In case that B is phenyl and carries two substituents R⁸, these arepreferably bound in the 2- and 4-positions, relative to the 1-positionof the attachment point of B to the remainder of the molecule (i.e. tothe sulfonyl group).

In case that B is phenyl and carries three substituents R⁸, these arepreferably bound in the 2-, 4- and 6-positions, relative to the1-position of the attachment point of B to the remainder of the molecule(i.e. to the sulfonyl group).

R¹ is preferably selected from halogen and cyano, and in particular fromcyano, fluorine and chlorine. Specifically, R¹ is cyano.

R² is preferably selected from hydrogen and halogen, and in particularfrom hydrogen and fluorine.

R³ and R⁴, independently of each other and independently of eachoccurrence, are preferably selected from halogen and C₁-C₄-alkyl, and inparticular from F, Cl and CH₃, with the proviso that R³ and R⁴ are nothalogen if they are bound to a carbon atom in α-position to a nitrogenring atom; and are in particular CH₃.

R⁵ is preferably selected from hydrogen, C₁-C₆-alkyl, fluorinatedC₁-C₆-alkyl, C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl, C₁-C₆-alkylwhich carries one substituent R¹¹; phenyl which may carry 1, 2 or 3substituents R¹²; a 3-, 4-, 5-, 6- or 7-membered saturated, partiallyunsaturated or maximally unsaturated heteromonocyclic ring containing 1,2 or 3 heteroatoms or heteroatom groups selected from O, N, S, NO, SOand SO₂ as ring members; and a 5-, 6-, 7-, 8-, 9-, 10- or 11-memberedsaturated, partially unsaturated or maximally unsaturated heterobicyclicring containing 1, 2 or 3 heteroatoms or heteroatom groups selected fromO, N, S, NO, SO and SO₂ as ring members, where the heteromonocyclic orheterobicyclic ring may carry 1, 2 or 3 substituents R¹²; and in casethat R⁵ is bound to a carbon ring atom, it is additionally selected from—OR¹³; where R¹¹, R¹² and R¹³ have one of the above general or, inparticular, one of the below preferred meanings.

More preferably, R⁵ is selected from hydrogen, C₁-C₆-alkyl, fluorinatedC₁-C₆-alkyl, C₁-C₆-alkyl which carries one substituent R¹¹; a 3-, 4-, 5-or 6-membered saturated heteromonocyclic ring containing 1 or 2heteroatoms or heteroatom groups selected from O, N, S, NO, SO and SO₂as ring members; and a 7-, 8-, 9-, 10- or 11-membered saturatedheterobicyclic ring containing 1 or 2 heteroatoms or heteroatom groupsselected from O, N, S, NO, SO and SO₂ as ring members, where theheteromonocyclic or heterobicyclic ring may carry 1, 2 or 3 substituentsR¹²; and in case that R⁵ is bound to a carbon ring atom, it isadditionally selected from —OR¹³; where R¹¹, R¹² and R¹³ have one of theabove general or, in particular, one of the below preferred meanings.

In particular, R⁵ is selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-alkylwhich carries one substituent R¹¹; a 4-, 5- or 6-membered saturatedheteromonocyclic ring containing 1 or 2 heteroatoms selected from O, Nand S as ring members; and a 7-, 8-, 9-, 10- or 11-membered saturatedheterobicyclic spiro ring containing 1 or 2 heteroatoms selected from O,N and S as ring members, where the heteromonocyclic or heterobicyclicring may carry 1 or 2 substituents R¹²; and in case that R⁵ is bound toa carbon ring atom, it is additionally selected from —OR¹³; where R¹¹,R¹² and R¹³ have one of the above general or, in particular, one of thebelow preferred meanings.

The 4-, 5- or 6-membered saturated heteromonocyclic ring R⁵ containing 1or 2 heteroatoms selected from O, N and S as ring members is inparticular selected from oxetan-3-yl, azetidin-3-yl, pyrrolidin-3-yl,piperidin-4-yl, piperazin-1-yl and morpholin-4-yl, and specifically fromoxetan-3-yl, azetidin-3-yl, piperidin-4-yl, piperazin-1-yl andmorpholin-4-yl.

The 7-, 8-, 9-, 10- or 11-membered saturated heterobicyclic spiro ringR⁵ containing 1 or 2 heteroatoms selected from O, N and S as ringmembers is in particular selected from the following bicyclic radicals:

and is specifically

R¹¹ is preferably selected from cyano, —OR¹³; NR¹⁴R¹⁵; a 3-, 4-, 5-, 6-or 7-membered saturated heteromonocyclic ring containing 1, 2 or 3heteroatoms or heteroatom groups selected from O, N, S, NO, SO and SO₂as ring members, and a 5-, 6-, 7-, 8-, 9-, 10- or 11-membered saturatedheterobicyclic ring containing 1, 2 or 3 heteroatoms or heteroatomgroups selected from O, N, S, NO, SO and SO₂ as ring members, where theheteromoncyclic or heterobicyclic ring may carry 1, 2 or 3 substituentsR¹²; and as a substituent on a cycloalkyl ring, R¹¹ is additionallyselected from C₁-C₄-alkyl and C₁-C₄-haloalkyl; where R¹², R¹³, R¹⁴ andR¹⁵ have one of the above general or, in particular, one of the belowpreferred meanings.

In particular, R¹¹ is selected from NR¹⁴R¹⁵, where R¹⁴ and R¹⁵ areindependently selected from hydrogen and C₁-C₄-alkyl; and a 4-, 5- or6-membered saturated heteromonocyclic ring containing 1 or 2 heteroatomsor heteroatom groups selected from O, N, S, NO, SO and SO₂ as ringmembers, where the heteromonocyclic ring may carry 1 or 2 or 3substituents R¹², where R¹² has one of the above general or, inparticular, one of the below preferred meanings.

The 4-, 5- or 6-membered saturated heteromonocyclic ring R¹¹ containing1 or 2 heteroatoms selected from O, N, S, NO, SO and SO₂ as ring membersis in particular selected from oxetan-3-yl, azetidin-1-yl,azetidin-3-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-1-yl,piperidin-4-yl, piperazin-1-yl, and morpholin-4-yl, and specificallyfrom piperidin-1-yl, piperazin-1-yl and morpholin-4-yl.

R¹² is preferably selected from halogen, cyano, C₁-C₄-alkyl, fluorinatedC₁-C₄-alkyl, C₁-C₄-alkoxy, fluorinated C₁-C₄-alkoxy, phenyl which maycarry 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano,C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinatedC₁-C₄-alkoxy; and a 3-, 4-, 5- or 6-membered saturated heteromonocyclicring containing 1, 2 or 3 heteroatoms or heteroatom groups selected fromO, N, S, NO, SO and SO₂ as ring members, where the heteromonocyclic ringmay carry 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano,C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinatedC₁-C₄-alkoxy, and in particular from C₁-C₄-alkyl, fluorinatedC₁-C₄-alkyl, and a 3-, 4-, 5- or 6-membered saturated heteromonocyclicring containing 1 or 2 heteroatoms selected from O, N and S as ringmembers.

The 3-, 4-, 5- or 6-membered saturated heteromonocyclic ring R¹² is inparticular selected from oxetan-3-yl, azetidin-3-yl, pyrrolidin-3-yl,piperidin-4-yl, piperazin-1-yl, and morpholin-4-yl, and is specificallyfrom oxetan-3-yl.

R¹³ is preferably selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyland C₁-C₄-alkyl which carries one substituent R¹⁷; and is in particularC₁-C₄-alkyl which carries one substituent R¹⁷; where R¹⁷ has one of theabove general or, in particular, one of the below preferred meanings.

R¹⁷ is preferably selected from NR¹⁴R¹⁵; phenyl which may carry 1, 2 or3 substituents R¹²; and a 3-, 4-, 5-, 6- or 7-membered saturated,partially unsaturated or maximally unsaturated heteromonocyclic ringcontaining 1, 2 or 3 heteroatoms or heteroatom groups selected from O,N, S, NO, SO and SO₂ as ring members; where R¹⁴ and R¹⁵ have one of theabove general or, in particular, one of the below preferred meanings.More preferably R¹⁷ is a 3-, 4-, 5- or 6-membered saturatedheteromonocyclic ring containing 1, 2 or 3 heteroatoms or heteroatomgroups selected from O, N, S, NO, SO and SO₂ as ring members, and inparticular a 6-membered saturated heteromonocyclic ring containing 1 or2 heteroatoms or heteroatom groups selected from O, N and S, such aspiperidin-1-yl, piperazin-1-yl or, especially, morpholin-4-yl.

R⁶ is preferably C₁-C₃-alkoxy, preferably methoxy, ethoxy or isopropoxy;and in particular methoxy or ethoxy.

R⁷ is preferably halogen or C₁-C₃-alkoxy, in particular fluorine ormethoxy.

Preferably each R⁸ is independently selected from halogen, cyano,C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl, C₁-C₃-alkoxy and fluorinatedC₁-C₃-alkoxy, more preferably from fluorine, cyano, methyl, methoxy andtrifluoromethoxy, and in particular from fluorine, cyano, methyl andmethoxy.

Preferably, a is 0 or 1, and in particular 0.

Preferably, b is 0 or 1, and in particular 0.

In a particular embodiment, the compound of formula I is a compound offormula IA

where

-   X¹, X², X⁷, R¹, R², R³, R⁴, R⁵, R⁶, a and b have one of the above    general or, in particular, one of the above preferred definitions    (to be however more precise, X⁷ is CH or N);-   X⁸ is N or CH;-   X⁹ is N or C—R^(8a);-   R^(7a) and R^(7b), independently of each other, are hydrogen or have    one of the general or, in particular, one of the preferred    definitions given above for R⁷; and are in particular hydrogen;-   R^(8a), R^(8b) and R^(8c), independently of each other, are hydrogen    or have one of the general or, in particular, one of the preferred    definitions given above for R⁸; and-   m, n, o and p are independently of each other 1 or 2.

Preferably, m and n are both 1 or are both 2.

Preferably, o and p are both 1 or are both 2.

The invention preferably relates to compounds of the formula 1A in which

-   X¹ is NH or CH₂;-   X² is N or CH;-   X⁷ is N or CH;-   X⁸ is N or CH;-   X⁹ is N or CR^(8a);-   R¹ is halogen or cyano;-   R² is hydrogen or halogen;-   R³ and R⁴, independently of each other and independently of each    occurrence, are selected from halogen and C₁-C₄-alkyl, with the    proviso that R³ and R⁴ are not halogen if they are bound to a carbon    atom in α-position to a nitrogen ring atom; and are in particular    CH₃;-   R⁵ is selected from hydrogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl, C₁-C₆-alkyl which    carries one substituent R¹¹; phenyl which may carry 1, 2 or 3    substituents R¹²; a 3-, 4-, 5-, 6- or 7-membered saturated,    partially unsaturated or maximally unsaturated heteromonocyclic ring    containing 1, 2 or 3 heteroatoms or heteroatom groups selected from    O, N, S, NO, SO and SO₂ as ring members; and a 5-, 6-, 7-, 8-, 9-,    10- or 11-membered saturated, partially unsaturated or maximally    unsaturated heterobicyclic ring containing 1, 2 or 3 heteroatoms or    heteroatom groups selected from O, N, S, NO, SO and SO₂ as ring    members, where the heteromonocyclic or heterobicyclic ring may carry    1, 2 or 3 substituents R¹²; and in case that X⁷ is CH, R⁵ is    additionally selected from —OR¹³;-   R⁶ is C₁-C₃-alkoxy;-   R^(7a) and R^(7b), independently of each other, are hydrogen,    halogen or C₁-C₃-alkoxy;-   R^(8a) (if present), R^(8b) and R^(8c), independently of each other,    are selected from hydrogen, halogen, cyano, C₁-C₃-alkyl, fluorinated    C₁-C₃-alkyl, C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy;-   R¹¹ is selected from cyano, —OR¹³; NR¹⁴R¹⁵; a 3-, 4-, 5-, 6- or    7-membered saturated heteromonocyclic ring containing 1, 2 or 3    heteroatoms or heteroatom groups selected from O, N, S, NO, SO and    SO₂ as ring members, and a 5-, 6-, 7-, 8-, 9-, 10- or 11-membered    saturated heterobicyclic ring containing 1, 2 or 3 heteroatoms or    heteroatom groups selected from O, N, S, NO, SO and SO₂ as ring    members, where the heteromonocyclic or heterobicyclic ring may carry    1, 2 or 3 substituents R¹²; and as a substituent on a cycloalkyl    ring, R¹¹ is additionally selected from C₁-C₄-alkyl and    C₁-C₄-haloalkyl;-   R¹² is selected from halogen, cyano, C₁-C₄-alkyl, fluorinated    C₁-C₄-alkyl, C₁-C₄-alkoxy, fluorinated C₁-C₄-alkoxy, phenyl which    may carry 1, 2 or 3 substituents selected from halogen, hydroxyl,    cyano, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and    fluorinated C₁-C₄-alkoxy; and a 3-, 4-, 5- or 6-membered saturated    heteromonocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom    groups selected from O, N, S, NO, SO and SO₂ as ring members, where    the heteromonocyclic ring may carry 1, 2 or 3 substituents selected    from halogen, hydroxyl, cyano, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl,    C₁-C₄-alkoxy and fluorinated C₁-C₄-alkoxy;-   R¹³ is selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and    C₁-C₄-alkyl which carries one substituent R¹⁷;-   R¹⁴ and R¹⁵, independently of each other, are selected from hydrogen    and C₁-C₄-alkyl;-   R¹⁷ is selected from NR¹⁴R¹⁵; phenyl which may carry 1, 2 or 3    substituents R¹²; and a 3-, 4-, 5-, 6- or 7-membered saturated,    partially unsaturated or maximally unsaturated heteromonocyclic ring    containing 1, 2 or 3 heteroatoms or heteroatom groups selected from    O, N, S, NO, SO and SO₂ as ring members;-   a is 0or 1;-   b is 0or 1;-   m and n are both 1 or are both 2; and-   o and p are both 1 or are both 2.

The invention more preferably relates to compounds of the formula IA inwhich

-   X¹ is NH or CH₂;-   X² is N or CH;-   X⁷ is N or CH;-   X⁸ is N or CH;-   X⁹ is N or CR^(8a);-   R¹ is cyano, fluorine or chlorine;-   R² is hydrogen or fluorine;-   R⁵ is selected from hydrogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₁-C₆-alkyl which carries one substituent R¹¹; a 3-, 4-, 5- or    6-membered saturated heteromonocyclic ring containing 1 or 2    heteroatoms or heteroatom groups selected from O, N, S, NO, SO and    SO₂ as ring members; and a 7-, 8-, 9-, 10- or 11-membered saturated    heterobicyclic ring containing 1 or 2 heteroatoms or heteroatom    groups selected from O, N, S, NO, SO and SO₂ as ring members, where    the heteromonocyclic or heterobicyclic ring may carry 1, 2 or 3    substituents R¹²; and in case that X⁷ is CH, R⁵ is additionally    selected from —OR¹³;-   R⁶ is methoxy, ethoxy or isopropoxy;-   R^(7a) and R^(7b), independently of each other, are hydrogen,    fluorine or methoxy;-   R^(8a) (if present), R^(8b) and R^(8c), independently of each other,    are selected from hydrogen, fluorine, cyano, methyl, methoxy and    trifluoromethoxy;-   R¹¹ is selected from NR¹⁴R¹⁵ and a 4-, 5- or 6-membered saturated    heteromonocyclic ring containing 1 or 2 heteroatoms or heteroatom    groups selected from O, N, S, NO, SO and SO₂ as ring members, where    the heteromonocyclic ring may carry 1 or 2 or 3 substituents R¹²;-   R¹² is selected from C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, and a 3-,    4-, 5- or 6-membered saturated heteromonocyclic ring containing 1 or    2 heteroatoms selected from O, N and S as ring members;-   R¹³ is selected C₁-C₄-alkyl which carries one substituent R¹⁷;-   R¹⁴ and R¹⁵ are independently selected from hydrogen and    C₁-C₄-alkyl;-   R¹⁷ is a 3-, 4-, 5- or 6-membered saturated heteromonocyclic ring    containing 1, 2 or 3 heteroatoms or heteroatom groups selected from    O, N, S, NO, SO and SO₂ as ring members;-   a is 0;-   b is 0;-   m and n are both 1 or are both 2; and-   o and p are both 1 or are both 2.

In particular, the invention relates to compounds of the formula IA inwhich

-   X¹ is NH or CH₂;-   X² is N or CH;-   X⁷ is N or CH;-   X⁸ is N or CH;-   X⁹ is N or CR^(8a);-   R¹ is cyano;-   R² is hydrogen or fluorine;-   R⁵ is selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyl which carries    one substituent R¹¹; a 4-, 5- or 6-membered saturated    heteromonocyclic ring containing 1 or 2 heteroatoms selected from O,    N and S as ring members; and a 7-, 8-, 9-, 10- or 11-membered    saturated heterobicyclic spiro ring containing 1 or 2 heteroatoms    selected from O, N and S as ring members, where the heteromonocyclic    or heterobicyclic ring may carry 1 or 2 substituents R¹²; and in    case that X⁷ is CH, R⁵ is additionally selected from —OR¹³;-   R⁶ is methoxy or ethoxy;-   R^(7a) and R^(7b) are hydrogen;-   R^(8a) (if present) and R^(8b), independently of each other, are    selected from hydrogen, fluorine, cyano, methyl and methoxy;-   R^(8c) is hydrogen;-   R¹¹ is selected from NR¹⁴R¹⁵ and a 4-, 5- or 6-membered saturated    heteromonocyclic ring containing 1 or 2 heteroatoms or heteroatom    groups selected from O, N, S, NO, SO and SO₂ as ring members, where    the heteromonocyclic ring may carry 1 or 2 or 3 substituents R¹²;-   R¹² is selected from C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, and a 3-,    4-, 5- or 6-membered saturated heteromonocyclic ring containing 1 or    2 heteroatoms selected from O, N and S as ring members;-   R¹³ is selected C₁-C₄-alkyl which carries one substituent R¹⁷;-   R¹⁴ and R¹⁵ are independently selected from hydrogen and    C₁-C₄-alkyl;-   R¹⁷ is a 6-membered saturated heteromonocyclic ring containing 1 or    2 heteroatoms or heteroatom groups selected from O, N and S;-   a is 0;-   b is 0;-   m and n are both 1 or are both 2; and-   o and p are both 1 or are both 2.

Examples of preferred embodiments of the present invention are compoundsof the formulae I.1 to I.128 and the N-oxides, stereoisomers(inclusively the conformers) and the pharmaceutically acceptable saltsthereof, in which the radicals X¹, R¹, R², R⁵, R^(8a), R^(8b) and R^(8c)have one of the above general or preferred meanings. In particular,preferred compounds are the individual compounds compiled in the tables1 to 53760 below.

Moreover, the meanings mentioned below for the individual variables inthe tables are per se, independently of the combination in which theyare mentioned, a particularly preferred embodiment of the substituentsin question.

Table 1

Compounds of the formula I.1 in which X¹ is NH, R⁵ is hydrogen, and R¹,R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case toone row of Table A

Table 2

Compounds of the formula I.1 in which X¹ is NH, R⁵ is methyl, and R¹,R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case toone row of Table A

Table 3

Compounds of the formula I.1 in which X¹ is NH, R⁵ is ethyl, and R¹, R²,R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case to onerow of Table A

Table 4

Compounds of the formula I.1 in which X¹ is NH, R⁵ is n-propyl, and R¹,R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case toone row of Table A

Table 5

Compounds of the formula I.1 in which X¹ is NH, R⁵ is isopropyl, and R¹,R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case toone row of Table A

Table 6

Compounds of the formula I.1 in which X¹ is NH, R⁵ is n-butyl, and R¹,R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case toone row of Table A

Table 7

Compounds of the formula I.1 in which X¹ is NH, R⁵ is sec-butyl, and R¹,R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case toone row of Table A

Table 8

Compounds of the formula I.1 in which X¹ is NH, R⁵ is isobutyl, and R¹,R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case toone row of Table A

Table 9

Compounds of the formula I.1 in which X¹ is NH, R⁵ is tert-butyl, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 10

Compounds of the formula I.1 in which X¹ is NH, R⁵ is CH₂CHF₂, and R¹,R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case toone row of Table A

Table 11

Compounds of the formula I.1 in which X¹ is NH, R⁵ is CH₂CF₃, and R¹,R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case toone row of Table A

Table 12

Compounds of the formula I.1 in which X¹ is NH, R⁵ is cyclopropyl, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 13

Compounds of the formula I.1 in which X¹ is NH, R⁵ is cyclobutyl, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 14

Compounds of the formula I.1 in which X¹ is NH, R⁵ is cyclopentyl, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 15

Compounds of the formula I.1 in which X¹ is NH, R⁵ is cyclohexyl, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 16

Compounds of the formula I.1 in which X¹ is NH, R⁵ is oxetan-3-yl, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 17

Compounds of the formula I.1 in which X¹ is NH, R⁵ is azetidin-3-yl, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 18

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-methylazetidin-3-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 19

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-ethylazetidin-3-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 20

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-propylazetidin-3-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 21

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-isopropylazetidin-3-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 22

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-(oxetan-3-yl)-azetidin-3-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) fora compound corresponds in each case to one row of Table A

Table 23

Compounds of the formula I.1 in which X¹ is NH, R⁵ is pyrrolidin-3-yl,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 24

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-methylpyrrolidin-3-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 25

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-ethylpyrrolidin-3-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 26

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-propylpyrrolidin-3-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 27

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-isopropylpyrrolidin-3-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 28

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-(oxetan-3-yl)-pyrrolidin-3-yl, and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 29

Compounds of the formula I.1 in which X¹ is NH, R⁵ is piperidin-4-yl,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 30

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-methylpiperidin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 31

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-ethylpiperidin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 32

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-propylpiperidin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 33

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-isopropylpiperidin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 34

Compounds of the formula I.1 in which X¹ is NH, R⁵ is1-(oxetan-3-yl)-piperidin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 35

Table 36

Compounds of the formula I.1 in which X¹ is NH, R⁵ is2-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 37

Compounds of the formula I.1 in which X¹ is NH, R⁵ is2-methyl-2-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 38

Compounds of the formula I.1 in which X¹ is NH, R⁵ is2-ethyl-2-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 39

Compounds of the formula I.1 in which X¹ is NH, R⁵ is2-propyl-2-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 40

Compounds of the formula I.1 in which X¹ is NH, R⁵ is2-isopropyl-2-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 41

Compounds of the formula I.1 in which X¹ is NH, R⁵ is2-(oxetan-3-yl)-2-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b)and R^(8c) for a compound corresponds in each case to one row of Table A

Table 42

Compounds of the formula I.1 in which X¹ is NH, R⁵ is2-(azetidin-3-yl)-2-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a),R^(8b) and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 43

Compounds of the formula I.1 in which X¹ is NH, R⁵ is —CH₂CH₂—NH₂, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 44

Compounds of the formula I.1 in which X¹ is NH, R⁵ is —(CH₂)₃—NH₂, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 45

Compounds of the formula I.1 in which X¹ is NH, R⁵ is —CH₂CH₂—N(H)CH₃,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 46

Compounds of the formula I.1 in which X¹ is NH, R⁵ is —(CH₂)₃—N(H)CH₃,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 47

Compounds of the formula I.1 in which X¹ is NH, R⁵ is —CH₂CH₂—N(CH₃)₂,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 48

Compounds of the formula I.1 in which X¹ is NH, R⁵ is —(CH₂)₃—N(CH₃)₂,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 49

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂—N(H)CH₂CH₃, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Table 50

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃—N(H)CH₂CH₃, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Table 51

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂—N(CH₂CH₃)₂, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Table 52

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃—N(CH₂CH₃)₂, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Table 53

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂—N(H)CH₂CH₂CH₃, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 54

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃—N(H)CH₂CH₂CH₃, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 55

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂—N(CH₂CH₂CH₃)₂, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 56

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃—N(CH₂CH₂CH₃)₂, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 57

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-aziridin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 58

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-azetidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 59

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-pyrrolidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 60

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-piperidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 61

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-piperazin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 62

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(1-methylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 63

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(1-ethylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 64

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(1-propylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 65

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(1-isopropylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 66

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(1-(oxetan-3-yl)-piperazin-4-yl), and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 67

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-morpholin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 68

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(2-oxa-6-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b)and R^(8c) for a compound corresponds in each case to one row of Table A

Table 69

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(2-aza-spiro[3.3]heptan-2-yl), and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 70

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(2,6-di-aza-spiro[3.3]heptan-2-yl), and R¹, R², R^(8a), R^(8b)and R^(8c) for a compound corresponds in each case to one row of Table A

Table 71

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(2-methyl-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R², R^(8a),R^(8b) and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 72

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(2-ethyl-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R², R^(8a),R^(8b) and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 73

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(2-propyl-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R², R^(8a),R^(8b) and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 74

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(2-isopropyl-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R²,R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case to onerow of Table A

Table 75

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—CH₂CH₂-(2-(oxetan-3-yl)-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R²,R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case to onerow of Table A

Table 76

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-aziridin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 77

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-azetidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 78

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-pyrrolidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 79

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-piperidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 80

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-piperazin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 81

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(1-methylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 82

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(1-ethylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 83

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(1-propylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 84

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(1-isopropylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 85

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(1-(oxetan-3-yl)-piperazin-4-yl), and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 86

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-morpholin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 87

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(2-oxa-6-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b)and R^(8c) for a compound corresponds in each case to one row of Table A

Table 88

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(2-aza-spiro[3.3]heptan-2-yl), and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 89

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(2,6-di-aza-spiro[3.3]heptan-2-yl), and R¹, R², R^(8a), R^(8b)and R^(8c) for a compound corresponds in each case to one row of Table A

Table 90

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(2-methyl-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R², R^(8a),R^(8b) and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 91

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(2-ethyl-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R², R^(8a),R^(8b) and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 92

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(2-propyl-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R², R^(8a),R^(8b) and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 93

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(2-isopropyl-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R²,R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case to onerow of Table A

Table 94

Compounds of the formula I.1 in which X¹ is NH, R⁵ is—(CH₂)₃-(2-(oxetan-3-yl)-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R²,R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case to onerow of Table A

Table 95

Compounds of the formula I.1 in which X¹ is NH, R⁵ is —CH₂CH₂—OCH₃, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 96

Compounds of the formula I.1 in which X¹ is NH, R⁵ is —CH₂CH₂—OCH₂CH₃,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 97

Compounds of the formula I.1 in which X¹ is NH, R⁵ is —CH₂CH₂—OCH(CH₃)₂,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 98

Compounds of the formula I.1 in which X¹ is NH, R⁵ is —(CH₂)₃—OCH₃, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 99

Compounds of the formula I.1 in which X¹ is NH, R⁵ is —(CH₂)₃—OCH₂CH₃,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 100

Compounds of the formula I.1 in which X¹ is NH, R⁵ is —(CH₂)₃—OCH(CH₃)₂,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Tables 101 to 200

Compounds of the formula I.1 in which X¹ is CH₂, R⁵ is as defined intables 1 to 100 and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 201 to 300

Compounds of the formula I.1 in which X¹ is O, R⁵ is as defined intables 1 to 100 and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 301 to 600

Compounds of the formula I.2 in which the combination of X¹ and R⁵ is asdefined in tables 1 to 300 and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 601

Compounds of the formula I.2 in which X¹ is NH, R⁵ is CH₂F, and R¹, R²,R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case to onerow of Table A

Table 602

Compounds of the formula I.2 in which X¹ is NH, R⁵ is CHF₂, and R¹, R²,R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case to onerow of Table A

Table 603 Compounds of the formula I.2 in which X¹ is NH, R⁵ is CF₃, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 604

Compounds of the formula I.2 in which X¹ is NH, R⁵ is CF₂CF₃, and R¹,R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case toone row of Table A

Table 605

Compounds of the formula I.2 in which X¹ is NH, R⁵ is oxiran-2-yl, andR¹, and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 606

Compounds of the formula I.2 in which X¹ is NH, R⁵ is aziridin-1-yl, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 607

Compounds of the formula I.2 in which X¹ is NH, R⁵ is aziridin-2-yl, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 608

Compounds of the formula I.2 in which X¹ is NH, R⁵ is1-methylaziridin-2-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 609

Compounds of the formula I.2 in which X¹ is NH, R⁵ is1-ethylaziridin-2-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 610

Compounds of the formula I.2 in which X¹ is NH, R⁵ is1-propylaziridin-2-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 611

Compounds of the formula I.2 in which X¹ is NH, R⁵ is1-isopropylaziridin-2-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 612

Compounds of the formula I.2 in which X¹ is NH, R⁵ is1-(oxetan-3-yl)-aziridin-2-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) fora compound corresponds in each case to one row of Table A

Table 613

Compounds of the formula I.2 in which X¹ is NH, R⁵ is azetidin-1-yl, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 614

Compounds of the formula I.2 in which X¹ is NH, R⁵ is piperdin-1-yl, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 615

Compounds of the formula I.2 in which X¹ is NH, R⁵ is piperdin-1-yl, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 616

Compounds of the formula I.2 in which X¹ is NH, R⁵ is piperazin-1-yl,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 617

Compounds of the formula I.2 in which X¹ is NH, R⁵ is1-methylpiperazin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 618

Compounds of the formula I.2 in which X¹ is NH, R⁵ is1-ethylpiperazin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 619

Compounds of the formula I.2 in which X¹ is NH, R⁵ is1-propylpiperazin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 620

Compounds of the formula I.2 in which X¹ is NH, R⁵ is1-isopropylpiperazin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 621

Compounds of the formula I.2 in which X¹ is NH, R⁵ is1-(oxetan-3-yl)-piperazin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 622

Compounds of the formula I.2 in which X¹ is NH, R⁵ is morpholin-4-yl,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 623

Compounds of the formula I.2 in which X¹ is NH, R⁵ is2-oxa-6-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 624

Compounds of the formula I.2 in which X¹ is NH, R⁵ is2-aza-spiro[3.3]heptan-2-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 625

Compounds of the formula I.2 in which X¹ is NH, R⁵ is2,6-di-aza-spiro[3.3]heptan-2-yl, and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 626

Compounds of the formula I.2 in which X¹ is NH, R⁵ is2-methyl-2,6-di-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b)and R^(8c) for a compound corresponds in each case to one row of Table A

Table 627

Compounds of the formula I.2 in which X¹ is NH, R⁵ is2-ethyl-2,6-di-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 628

Compounds of the formula I.2 in which X¹ is NH, R⁵ is2-propyl-2,6-di-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b)and R^(8c) for a compound corresponds in each case to one row of Table A

Table 629

Compounds of the formula I.2 in which X¹ is NH, R⁵ is2-isopropyl-2,6-di-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a), R^(8b)and R^(8c) for a compound corresponds in each case to one row of Table A

Table 630

Compounds of the formula I.2 in which X¹ is NH, R⁵ is2-(oxetan-3-yl)-2,6-di-aza-spiro[3.3]heptan-6-yl, and R¹, R², R^(8a),R^(8b) and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 631

Compounds of the formula I.2 in which X¹ is NH, R⁵ is —CH₂—NH₂, and R¹,R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case toone row of Table A

Table 632

Compounds of the formula I.2 in which X¹ is NH, R⁵ is —CH₂—N(H)CH₃, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 633 Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂—N(CH₃)₂, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Table 634

Compounds of the formula I.2 in which X¹ is NH, R⁵ is —CH₂—N(H)CH₂CH₃,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 635

Compounds of the formula I.2 in which X¹ is NH, R⁵ is —CH₂—N(CH₂CH₃)₂,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 636

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂—N(H)CH₂CH₂CH₃, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Table 637

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂—N(CH₂CH₂CH₃)₂, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Table 638

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-aziridin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Table 639

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-azetidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Table 640

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-pyrrolidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 641

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-piperidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 642

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-piperazin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 643

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(1-methylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c) fora compound corresponds in each case to one row of Table A

Table 644

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(1-ethylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c) fora compound corresponds in each case to one row of Table A

Table 645

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(1-propylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c) fora compound corresponds in each case to one row of Table A

Table 646

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(1-isopropylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 647

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(1-(oxetan-3-yl)-piperazin-4-yl), and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 648

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-azetidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Table 649

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-pyrrolidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 650

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-piperidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 651

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-piperazin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 652

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(1-methylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c) fora compound corresponds in each case to one row of Table A

Table 653

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(1-ethylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c) fora compound corresponds in each case to one row of Table A

Table 654

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(1-propylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c) fora compound corresponds in each case to one row of Table A

Table 655

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(1-isopropylpiperazin-4-yl), and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 656

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(1-(oxetan-3-yl)-piperazin-4-yl), and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 657

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-morpholin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 658

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(2-oxa-6-aza-spiro[3.3]heptan-6-yl), and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 659

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(2-aza-spiro[3.3]heptan-2-yl), and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 660

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(2,6-di-aza-spiro[3.3]heptan-2-yl), and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 661

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(2-methyl-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R², R^(8a),R^(8b) and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 662

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(2-ethyl-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R², R^(8a),R^(8b) and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 663

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(2-propyl-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R², R^(8a),R^(8b) and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 664

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(2-isopropyl-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R², R^(8a),R^(8b) and R^(8c) for a compound corresponds in each case to one row ofTable A

Table 665

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—CH₂-(2-(oxetan-3-yl)-2,6-di-aza-spiro[3.3]heptan-6-yl), and R¹, R²,R^(8a), R^(8b) and R^(8c) for a compound corresponds in each case to onerow of Table A

Table 666

Compounds of the formula I.2 in which X¹ is NH, R⁵ is —O—CH₂CH₂—NH₂, andR¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 667

Compounds of the formula I.2 in which X¹ is NH, R⁵ is —O—CH₂CH₂—NHCH₃,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 668

Compounds of the formula I.2 in which X¹ is NH, R⁵ is —O—CH₂CH₂—N(CH₃)₂,and R¹, R², R^(8a), R^(8b) and R^(8c) for a compound corresponds in eachcase to one row of Table A

Table 669

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—O—CH₂CH₂—N(H)CH₂CH₃, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 670

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—O—CH₂CH₂—N(CH₂CH₃)₂, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 671

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—O—CH₂CH₂-aziridin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 672

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—O—CH₂CH₂-azetidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 673

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—O—CH₂CH₂-pyrrolidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 674

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—O—CH₂CH₂-piperidin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 675

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—O—CH₂CH₂-piperazin-1-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Table 676

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—O—CH₂CH₂-(1-methylpiperazin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 677

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—O—CH₂CH₂-(1-ethylpiperazin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 678

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—O—CH₂CH₂-(1-propylpiperazin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c)for a compound corresponds in each case to one row of Table A

Table 679

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—O—CH₂CH₂-(1-isopropylpiperazin-4-yl, and R¹, R², R^(8a), R^(8b) andR^(8c) for a compound corresponds in each case to one row of Table A

Table 680

Compounds of the formula I.2 in which X¹ is NH, R⁵ is—O—CH₂CH₂-morpholin-4-yl, and R¹, R², R^(8a), R^(8b) and R^(8c) for acompound corresponds in each case to one row of Table A

Tables 681 to 760

Compounds of the formula I.2 in which X¹ is CH₂, R⁵ is as defined intables 601 to 680, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 761 to 840

Compounds of the formula I.2 in which X¹ is O, R⁵ is as defined intables 601 to 680, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 841 to 1140

Compounds of the formula I.3 in which X¹ and R⁵ are as defined in tables1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 1141 to 1680

Compounds of the formula I.4 in which X¹ and R⁵ are as defined in tables301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 1681 to 1980

Compounds of the formula I.5 in which X¹ and R⁵ are as defined in tables1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 1981 to 2520

Compounds of the formula I.6 in which X¹ and R⁵ are as defined in tables301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 2521 to 2820

Compounds of the formula I.7 in which X¹ and R⁵ are as defined in tables1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 2821 to 3360

Compounds of the formula I.8 in which X¹ and R⁵ are as defined in tables301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 3361 to 3660

Compounds of the formula I.9 in which X¹ and R⁵ are as defined in tables1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 3661 to 4200

Compounds of the formula I.10 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 4201 to 4500

Compounds of the formula I.11 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 4501 to 5040

Compounds of the formula I.12 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 5041 to 5340

Compounds of the formula I.13 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 5341 to 5880

Compounds of the formula I.14 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 5881 to 6180

Compounds of the formula I.15 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 6181 to 6720

Compounds of the formula I.16 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 6721 to 7020

Compounds of the formula I.17 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 7021 to 7560

Compounds of the formula I.18 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 7561 to 7860

Compounds of the formula I.19 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 7861 to 8400

Compounds of the formula I.20 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 8401 to 8700

Compounds of the formula I.21 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 8701 to 9240

Compounds of the formula I.22 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 9241 to 9540

Compounds of the formula I.23 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 9541 to 10080

Compounds of the formula I.24 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 10081 to 10380

Compounds of the formula I.25 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 10381 to 10920

Compounds of the formula I.26 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 10921 to 11220

Compounds of the formula I.27 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 11221 to 11760

Compounds of the formula I.28 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 11761 to 12060

Compounds of the formula I.29 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 12061 to 12600

Compounds of the formula I.30 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 12601 to 12900

Compounds of the formula I.31 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 12901 to 13440

Compounds of the formula I.32 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 13441 to 13740

Compounds of the formula I.33 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 13741 to 14280

Compounds of the formula I.34 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 14281 to 14580

Compounds of the formula I.35 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 14581 to 15120

Compounds of the formula I.36 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 15121 to 15420

Compounds of the formula I.37 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 15421 to 15960

Compounds of the formula I.38 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 15961 to 16260

Compounds of the formula I.39 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 16261 to 16800

Compounds of the formula I.40 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 16801 to 17100

Compounds of the formula I.41 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 17101 to 17640

Compounds of the formula I.42 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 17641 to 17940

Compounds of the formula I.43 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 17941 to 18480

Compounds of the formula I.44 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 18481 to 18780

Compounds of the formula I.45 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 18781 to 19320

Compounds of the formula I.46 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 19321 to 19620

Compounds of the formula I.47 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 19621 to 20160

Compounds of the formula I.48 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 20161 to 20460

Compounds of the formula I.49 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 20461 to 21000

Compounds of the formula I.50 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 21001 to 21300

Compounds of the formula I.51 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 21301 to 21840

Compounds of the formula I.52 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 21841 to 22140

Compounds of the formula I.53 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 22141 to 22680

Compounds of the formula I.54 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 22681 to 22980

Compounds of the formula I.55 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 22981 to 23520

Compounds of the formula I.56 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 23521 to 23820

Compounds of the formula I.57 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 23821 to 24360

Compounds of the formula I.58 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 24361 to 24660

Compounds of the formula I.59 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 24661 to 25200

Compounds of the formula I.60 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 25201 to 25500

Compounds of the formula I.61 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 25501 to 26040

Compounds of the formula I.62 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 26041 to 26340

Compounds of the formula I.63 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 26341 to 26880

Compounds of the formula I.64 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8a), R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table A

Tables 26881 to 27180

Compounds of the formula I.65 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 27181 to 27720

Compounds of the formula I.66 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 27721 to 28020

Compounds of the formula I.67 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 28021 to 28560

Compounds of the formula I.68 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 28561 to 28860

Compounds of the formula I.69 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 28861 to 29400

Compounds of the formula I.70 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 29401 to 29700

Compounds of the formula I.71 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 29701 to 30240

Compounds of the formula I.72 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 30241 to 30540

Compounds of the formula I.73 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 30541 to 31080

Compounds of the formula I.74 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 31081 to 31380

Compounds of the formula I.75 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 31381 to 31920

Compounds of the formula I.76 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 31921 to 32220

Compounds of the formula I.77 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 32221 to 32760

Compounds of the formula I.78 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 32761 to 33060

Compounds of the formula I.79 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 33061 to 33600

Compounds of the formula I.80 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 33601 to 33900

Compounds of the formula I.81 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 33901 to 34440

Compounds of the formula I.82 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 34441 to 34740

Compounds of the formula I.83 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 34741 to 35280

Compounds of the formula I.84 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 35281 to 35580

Compounds of the formula I.85 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 35581 to 36120

Compounds of the formula I.86 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 36121 to 36420

Compounds of the formula I.87 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 36421 to 36960

Compounds of the formula I.88 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 36961 to 37260

Compounds of the formula I.89 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 37261 to 37800

Compounds of the formula I.90 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 37801 to 38100

Compounds of the formula I.91 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 38101 to 38640

Compounds of the formula I.92 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 38641 to 38940

Compounds of the formula I.93 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 38941 to 39480

Compounds of the formula I.94 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 39481 to 39780

Compounds of the formula I.95 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 39781 to 40320

Compounds of the formula I.96 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 40321 to 40620

Compounds of the formula I.97 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 40621 to 41160

Compounds of the formula I.98 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 41161 to 41460

Compounds of the formula I.99 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 41461 to 42000

Compounds of the formula I.100 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 42001 to 42300

Compounds of the formula I.101 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 42301 to 42840

Compounds of the formula I.102 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 42841 to 43140

Compounds of the formula I.103 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 43141 to 43680

Compounds of the formula I.104 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 43681 to 43980

Compounds of the formula I.105 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 43981 to 44520

Compounds of the formula I.106 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 44521 to 44820

Compounds of the formula I.107 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 44821 to 45360

Compounds of the formula I.108 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 45361 to 45660

Compounds of the formula I.109 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 45661 to 46200

Compounds of the formula I.110 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 46201 to 46500

Compounds of the formula I.111 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 46501 to 47040

Compounds of the formula I.112 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 47041 to 47340

Compounds of the formula I.113 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 47341 to 47880

Compounds of the formula I.114 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 47881 to 48180

Compounds of the formula I.115 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 48181 to 48720

Compounds of the formula I.116 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 48721 to 49020

Compounds of the formula I.117 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 49021 to 49560

Compounds of the formula I.118 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 49561 to 49860

Compounds of the formula I.119 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 49861 to 50400

Compounds of the formula I.120 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 50401 to 50700

Compounds of the formula I.121 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 50701 to 51240

Compounds of the formula I.122 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 51241 to 51540

Compounds of the formula I.123 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 51541 to 52080

Compounds of the formula I.124 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 52081 to 52380

Compounds of the formula I.125 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 52381 to 52920

Compounds of the formula I.126 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 52921 to 53220

Compounds of the formula I.127 in which X¹ and R⁵ are as defined intables 1 to 300, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

Tables 53221 to 53760

Compounds of the formula I.128 in which X¹ and R⁵ are as defined intables 301 to 840, and R¹, R², R^(8b) and R^(8c) for a compoundcorresponds in each case to one row of Table B

TABLE A Example No. R^(8a) R^(8b) R^(8c) R¹ R² A-1. H H H CN H A-2. F HH CN H A-3. CH₃ H H CN H A-4. OCH₃ H H CN H A-5. CH₂F H H CN H A-6. CHF₂H H CN H A-7. CF₃ H H CN H A-8. OCH₂F H H CN H A-9. OCHF₂ H H CN H A-10.OCF₃ H H CN H A-11. H F H CN H A-12. H CH₃ H CN H A-13. H OCH₃ H CN HA-14. H CN H CN H A-15. H CH₂F H CN H A-16. H CHF₂ H CN H A-17. H CF₃ HCN H A-18. H OCH₂F H CN H A-19. H OCHF₂ H CN H A-20. H OCF₃ H CN H A-21.H H 3-F CN H A-22. H H 3-CH₃ CN H A-23. H H 3-OCH₃ CN H A-24. H H 5-F CNH A-25. H H 5-CH₃ CN H A-26. H H 5-OCH₃ CN H A-27. F F H CN H A-28. FCH₃ H CN H A-29. F OCH₃ H CN H A-30. F CN H CN H A-31. F CH₂F H CN HA-32. F CHF₂ H CN H A-33. F CF₃ H CN H A-34. F OCH₂F H CN H A-35. FOCHF₂ H CN H A-36. F OCF₃ H CN H A-37. F H 3-F CN H A-38. F H 3-CH₃ CN HA-39. F H 3-OCH₃ CN H A-40. F H 5-F CN H A-41. F H 5-CH₃ CN H A-42. F H5-OCH₃ CN H A-43. CH₃ F H CN H A-44. CH₃ CH₃ H CN H A-45. CH₃ OCH₃ H CNH A-46. CH₃ CN H CN H A-47. CH₃ CH₂F H CN H A-48. CH₃ CHF₂ H CN H A-49.CH₃ CF₃ H CN H A-50. CH₃ OCH₂F H CN H A-51. CH₃ OCHF₂ H CN H A-52. CH₃OCF₃ H CN H A-53. CH₃ H 3-F CN H A-54. CH₃ H 3-CH₃ CN H A-55. CH₃ H3-OCH₃ CN H A-56. CH₃ H 5-F CN H A-57. CH₃ H 5-CH₃ CN H A-58. CH₃ H5-OCH₃ CN H A-59. OCH₃ F H CN H A-60. OCH₃ CH₃ H CN H A-61. OCH₃ OCH₃ HCN H A-62. OCH₃ CN H CN H A-63. OCH₃ CH₂F H CN H A-64. OCH₃ CHF₂ H CN HA-65. OCH₃ CF₃ H CN H A-66. OCH₃ OCH₂F H CN H A-67. OCH₃ OCHF₂ H CN HA-68. OCH₃ OCF₃ H CN H A-69. OCH₃ H 3-F CN H A-70. OCH₃ H 3-CH₃ CN HA-71. OCH₃ H 3-OCH₃ CN H A-72. OCH₃ H 5-F CN H A-73. OCH₃ H 5-CH₃ CN HA-74. OCH₃ H 5-OCH₃ CN H A-75. H F 3-F CN H A-76. H F 3-CH₃ CN H A-77. HF 3-OCH₃ CN H A-78. H F 5-F CN H A-79. H F 5-CH₃ CN H A-80. H F 5-OCH₃CN H A-81. H CH₃ 3-F CN H A-82. H CH₃ 3-CH₃ CN H A-83. H CH₃ 3-OCH₃ CN HA-84. H CH₃ 5-F CN H A-85. H CH₃ 5-CH₃ CN H A-86. H CH₃ 5-OCH₃ CN HA-87. H OCH₃ 3-F CN H A-88. H OCH₃ 3-CH₃ CN H A-89. H OCH₃ 3-OCH₃ CN HA-90. H OCH₃ 5-F CN H A-91. H OCH₃ 5-CH₃ CN H A-92. H OCH₃ 5-OCH₃ CN HA-93. H CN 3-F CN H A-94. H CN 3-CH₃ CN H A-95. H CN 3-OCH₃ CN H A-96. HCN 5-F CN H A-97. H CN 5-CH₃ CN H A-98. H CN 5-OCH₃ CN H A-99. H CH₂F3-F CN H A-100. H CH₂F 3-CH₃ CN H A-101. H CH₂F 3-OCH₃ CN H A-102. HCH₂F 5-F CN H A-103. H CH₂F 5-CH₃ CN H A-104. H CH₂F 5-OCH₃ CN H A-105.H CHF₂ 3-F CN H A-106. H CHF₂ 3-CH₃ CN H A-107. H CHF₂ 3-OCH₃ CN HA-108. H CHF₂ 5-F CN H A-109. H CHF₂ 5-CH₃ CN H A-110. H CHF₂ 5-OCH₃ CNH A-111. H CF₃ 3-F CN H A-112. H CF₃ 3-CH₃ CN H A-113. H CF₃ 3-OCH₃ CN HA-114. H CF₃ 5-F CN H A-115. H CF₃ 5-CH₃ CN H A-116. H CF₃ 5-OCH₃ CN HA-117. H OCH₂F 3-F CN H A-118. H OCH₂F 3-CH₃ CN H A-119. H OCH₂F 3-OCH₃CN H A-120. H OCH₂F 5-F CN H A-121. H OCH₂F 5-CH₃ CN H A-122. H OCH₂F5-OCH₃ CN H A-123. H OCHF₂ 3-F CN H A-124. H OCHF₂ 3-CH₃ CN H A-125. HOCHF₂ 3-OCH₃ CN H A-126. H OCHF₂ 5-F CN H A-127. H OCHF₂ 5-CH₃ CN HA-128. H OCHF₂ 5-OCH₃ CN H A-129. H OCF₃ 3-F CN H A-130. H OCF₃ 3-CH₃ CNH A-131. H OCF₃ 3-OCH₃ CN H A-132. H OCF₃ 5-F CN H A-133. H OCF₃ 5-CH₃CN H A-134. H OCF₃ 5-OCH₃ CN H A-135. F F 3-F CN H A-136. F F 3-CH₃ CN HA-137. F F 3-OCH₃ CN H A-138. F F 5-F CN H A-139. F F 5-CH₃ CN H A-140.F F 5-OCH₃ CN H A-141. F CH₃ 3-F CN H A-142. F CH₃ 3-CH₃ CN H A-143. FCH₃ 3-OCH₃ CN H A-144. F CH₃ 5-F CN H A-145. F CH₃ 5-CH₃ CN H A-146. FCH₃ 5-OCH₃ CN H A-147. F OCH₃ 3-F CN H A-148. F OCH₃ 3-CH₃ CN H A-149. FOCH₃ 3-OCH₃ CN H A-150. F OCH₃ 5-F CN H A-151. F OCH₃ 5-CH₃ CN H A-152.F OCH₃ 5-OCH₃ CN H A-153. F CN 3-F CN H A-154. F CN 3-CH₃ CN H A-155. FCN 3-OCH₃ CN H A-156. F CN 5-F CN H A-157. F CN 5-CH₃ CN H A-158. F CN5-OCH₃ CN H A-159. F CH₂F 3-F CN H A-160. F CH₂F 3-CH₃ CN H A-161. FCH₂F 3-OCH₃ CN H A-162. F CH₂F 5-F CN H A-163. F CH₂F 5-CH₃ CN H A-164.F CH₂F 5-OCH₃ CN H A-165. F CHF₂ 3-F CN H A-166. F CHF₂ 3-CH₃ CN HA-167. F CHF₂ 3-OCH₃ CN H A-168. F CHF₂ 5-F CN H A-169. F CHF₂ 5-CH₃ CNH A-170. F CHF₂ 5-OCH₃ CN H A-171. F CF₃ 3-F CN H A-172. F CF₃ 3-CH₃ CNH A-173. F CF₃ 3-OCH₃ CN H A-174. F CF₃ 5-F CN H A-175. F CF₃ 5-CH₃ CN HA-176. F CF₃ 5-OCH₃ CN H A-177. F OCH₂F 3-F CN H A-178. F OCH₂F 3-CH₃ CNH A-179. F OCH₂F 3-OCH₃ CN H A-180. F OCH₂F 5-F CN H A-181. F OCH₂F5-CH₃ CN H A-182. F OCH₂F 5-OCH₃ CN H A-183. F OCHF₂ 3-F CN H A-184. FOCHF₂ 3-CH₃ CN H A-185. F OCHF₂ 3-OCH₃ CN H A-186. F OCHF₂ 5-F CN HA-187. F OCHF₂ 5-CH₃ CN H A-188. F OCHF₂ 5-OCH₃ CN H A-189. F OCF₃ 3-FCN H A-190. F OCF₃ 3-CH₃ CN H A-191. F OCF₃ 3-OCH₃ CN H A-192. F OCF₃5-F CN H A-193. F OCF₃ 5-CH₃ CN H A-194. F OCF₃ 5-OCH₃ CN H A-195. CH₃ F3-F CN H A-196. CH₃ F 3-CH₃ CN H A-197. CH₃ F 3-OCH₃ CN H A-198. CH₃ F5-F CN H A-199. CH₃ F 5-CH₃ CN H A-200. CH₃ F 5-OCH₃ CN H A-201. CH₃ CH₃3-F CN H A-202. CH₃ CH₃ 3-CH₃ CN H A-203. CH₃ CH₃ 3-OCH₃ CN H A-204. CH₃CH₃ 5-F CN H A-205. CH₃ CH₃ 5-CH₃ CN H A-206. CH₃ CH₃ 5-OCH₃ CN H A-207.CH₃ OCH₃ 3-F CN H A-208. CH₃ OCH₃ 3-CH₃ CN H A-209. CH₃ OCH₃ 3-OCH₃ CN HA-210. CH₃ OCH₃ 5-F CN H A-211. CH₃ OCH₃ 5-CH₃ CN H A-212. CH₃ OCH₃5-OCH₃ CN H A-213. CH₃ CN 3-F CN H A-214. CH₃ CN 3-CH₃ CN H A-215. CH₃CN 3-OCH₃ CN H A-216. CH₃ CN 5-F CN H A-217. CH₃ CN 5-CH₃ CN H A-218.CH₃ CN 5-OCH₃ CN H A-219. CH₃ CH₂F 3-F CN H A-220. CH₃ CH₂F 3-CH₃ CN HA-221. CH₃ CH₂F 3-OCH₃ CN H A-222. CH₃ CH₂F 5-F CN H A-223. CH₃ CH₂F5-CH₃ CN H A-224. CH₃ CH₂F 5-OCH₃ CN H A-225. CH₃ CHF₂ 3-F CN H A-226.CH₃ CHF₂ 3-CH₃ CN H A-227. CH₃ CHF₂ 3-OCH₃ CN H A-228. CH₃ CHF₂ 5-F CN HA-229. CH₃ CHF₂ 5-CH₃ CN H A-230. CH₃ CHF₂ 5-OCH₃ CN H A-231. CH₃ CF₃3-F CN H A-232. CH₃ CF₃ 3-CH₃ CN H A-233. CH₃ CF₃ 3-OCH₃ CN H A-234. CH₃CF₃ 5-F CN H A-235. CH₃ CF₃ 5-CH₃ CN H A-236. CH₃ CF₃ 5-OCH₃ CN H A-237.CH₃ OCH₂F 3-F CN H A-238. CH₃ OCH₂F 3-CH₃ CN H A-239. CH₃ OCH₂F 3-OCH₃CN H A-240. CH₃ OCH₂F 5-F CN H A-241. CH₃ OCH₂F 5-CH₃ CN H A-242. CH₃OCH₂F 5-OCH₃ CN H A-243. CH₃ OCHF₂ 3-F CN H A-244. CH₃ OCHF₂ 3-CH₃ CN HA-245. CH₃ OCHF₂ 3-OCH₃ CN H A-246. CH₃ OCHF₂ 5-F CN H A-247. CH₃ OCHF₂5-CH₃ CN H A-248. CH₃ OCHF₂ 5-OCH₃ CN H A-249. CH₃ OCF₃ 3-F CN H A-250.CH₃ OCF₃ 3-CH₃ CN H A-251. CH₃ OCF₃ 3-OCH₃ CN H A-252. CH₃ OCF₃ 5-F CN HA-253. CH₃ OCF₃ 5-CH₃ CN H A-254. CH₃ OCF₃ 5-OCH₃ CN H A-255. OCH₃ F 3-FCN H A-256. OCH₃ F 3-CH₃ CN H A-257. OCH₃ F 3-OCH₃ CN H A-258. OCH₃ F5-F CN H A-259. OCH₃ F 5-CH₃ CN H A-260. OCH₃ F 5-OCH₃ CN H A-261. OCH₃CH₃ 3-F CN H A-262. OCH₃ CH₃ 3-CH₃ CN H A-263. OCH₃ CH₃ 3-OCH₃ CN HA-264. OCH₃ CH₃ 5-F CN H A-265. OCH₃ CH₃ 5-CH₃ CN H A-266. OCH₃ CH₃5-OCH₃ CN H A-267. OCH₃ OCH₃ 3-F CN H A-268. OCH₃ OCH₃ 3-CH₃ CN H A-269.OCH₃ OCH₃ 3-OCH₃ CN H A-270. OCH₃ OCH₃ 5-F CN H A-271. OCH₃ OCH₃ 5-CH₃CN H A-272. OCH₃ OCH₃ 5-OCH₃ CN H A-273. OCH₃ CN 3-F CN H A-274. OCH₃ CN3-CH₃ CN H A-275. OCH₃ CN 3-OCH₃ CN H A-276. OCH₃ CN 5-F CN H A-277.OCH₃ CN 5-CH₃ CN H A-278. OCH₃ CN 5-OCH₃ CN H A-279. OCH₃ CH₂F 3-F CN HA-280. OCH₃ CH₂F 3-CH₃ CN H A-281. OCH₃ CH₂F 3-OCH₃ CN H A-282. OCH₃CH₂F 5-F CN H A-283. OCH₃ CH₂F 5-CH₃ CN H A-284. OCH₃ CH₂F 5-OCH₃ CN HA-285. OCH₃ CHF₂ 3-F CN H A-286. OCH₃ CHF₂ 3-CH₃ CN H A-287. OCH₃ CHF₂3-OCH₃ CN H A-288. OCH₃ CHF₂ 5-F CN H A-289. OCH₃ CHF₂ 5-CH₃ CN H A-290.OCH₃ CHF₂ 5-OCH₃ CN H A-291. OCH₃ CF₃ 3-F CN H A-292. OCH₃ CF₃ 3-CH₃ CNH A-293. OCH₃ CF₃ 3-OCH₃ CN H A-294. OCH₃ CF₃ 5-F CN H A-295. OCH₃ CF₃5-CH₃ CN H A-296. OCH₃ CF₃ 5-OCH₃ CN H A-297. OCH₃ OCH₂F 3-F CN H A-298.OCH₃ OCH₂F 3-CH₃ CN H A-299. OCH₃ OCH₂F 3-OCH₃ CN H A-300. OCH₃ OCH₂F5-F CN H A-301. OCH₃ OCH₂F 5-CH₃ CN H A-302. OCH₃ OCH₂F 5-OCH₃ CN HA-303. OCH₃ OCHF₂ 3-F CN H A-304. OCH₃ OCHF₂ 3-CH₃ CN H A-305. OCH₃OCHF₂ 3-OCH₃ CN H A-306. OCH₃ OCHF₂ 5-F CN H A-307. OCH₃ OCHF₂ 5-CH₃ CNH A-308. OCH₃ OCHF₂ 5-OCH₃ CN H A-309. OCH₃ OCF₃ 3-F CN H A-310. OCH₃OCF₃ 3-CH₃ CN H A-311. OCH₃ OCF₃ 3-OCH₃ CN H A-312. OCH₃ OCF₃ 5-F CN HA-313. OCH₃ OCF₃ 5-CH₃ CN H A-314. OCH₃ OCF₃ 5-OCH₃ CN H A-315. CH₂F F3-F CN H A-316. CH₂F F 3-CH₃ CN H A-317. CH₂F F 3-OCH₃ CN H A-318. CH₂FF 5-F CN H A-319. CH₂F F 5-CH₃ CN H A-320. CH₂F F 5-OCH₃ CN H A-321.CH₂F CH₃ 3-F CN H A-322. CH₂F CH₃ 3-CH₃ CN H A-323. CH₂F CH₃ 3-OCH₃ CN HA-324. CH₂F CH₃ 5-F CN H A-325. CH₂F CH₃ 5-CH₃ CN H A-326. CH₂F CH₃5-OCH₃ CN H A-327. CH₂F OCH₃ 3-F CN H A-328. CH₂F OCH₃ 3-CH₃ CN H A-329.CH₂F OCH₃ 3-OCH₃ CN H A-330. CH₂F OCH₃ 5-F CN H A-331. CH₂F OCH₃ 5-CH₃CN H A-332. CH₂F OCH₃ 5-OCH₃ CN H A-333. CH₂F CN 3-F CN H A-334. CH₂F CN3-CH₃ CN H A-335. CH₂F CN 3-OCH₃ CN H A-336. CH₂F CN 5-F CN H A-337.CH₂F CN 5-CH₃ CN H A-338. CH₂F CN 5-OCH₃ CN H A-339. CH₂F CH₂F 3-F CN HA-340. CH₂F CH₂F 3-CH₃ CN H A-341. CH₂F CH₂F 3-OCH₃ CN H A-342. CH₂FCH₂F 5-F CN H A-343. CH₂F CH₂F 5-CH₃ CN H A-344. CH₂F CH₂F 5-OCH₃ CN HA-345. CH₂F CHF₂ 3-F CN H A-346. CH₂F CHF₂ 3-CH₃ CN H A-347. CH₂F CHF₂3-OCH₃ CN H A-348. CH₂F CHF₂ 5-F CN H A-349. CH₂F CHF₂ 5-CH₃ CN H A-350.CH₂F CHF₂ 5-OCH₃ CN H A-351. CH₂F CF₃ 3-F CN H A-352. CH₂F CF₃ 3-CH₃ CNH A-353. CH₂F CF₃ 3-OCH₃ CN H A-354. CH₂F CF₃ 5-F CN H A-355. CH₂F CF₃5-CH₃ CN H A-356. CH₂F CF₃ 5-OCH₃ CN H A-357. CH₂F OCH₂F 3-F CN H A-358.CH₂F OCH₂F 3-CH₃ CN H A-359. CH₂F OCH₂F 3-OCH₃ CN H A-360. CH₂F OCH₂F5-F CN H A-361. CH₂F OCH₂F 5-CH₃ CN H A-362. CH₂F OCH₂F 5-OCH₃ CN HA-363. CH₂F OCHF₂ 3-F CN H A-364. CH₂F OCHF₂ 3-CH₃ CN H A-365. CH₂FOCHF₂ 3-OCH₃ CN H A-366. CH₂F OCHF₂ 5-F CN H A-367. CH₂F OCHF₂ 5-CH₃ CNH A-368. CH₂F OCHF₂ 5-OCH₃ CN H A-369. CH₂F OCF₃ 3-F CN H A-370. CH₂FOCF₃ 3-CH₃ CN H A-371. CH₂F OCF₃ 3-OCH₃ CN H A-372. CH₂F OCF₃ 5-F CN HA-373. CH₂F OCF₃ 5-CH₃ CN H A-374. CH₂F OCF₃ 5-OCH₃ CN H A-375. CHF₂ F3-F CN H A-376. CHF₂ F 3-CH₃ CN H A-377. CHF₂ F 3-OCH₃ CN H A-378. CHF₂F 5-F CN H A-379. CHF₂ F 5-CH₃ CN H A-380. CHF₂ F 5-OCH₃ CN H A-381.CHF₂ CH₃ 3-F CN H A-382. CHF₂ CH₃ 3-CH₃ CN H A-383. CHF₂ CH₃ 3-OCH₃ CN HA-384. CHF₂ CH₃ 5-F CN H A-385. CHF₂ CH₃ 5-CH₃ CN H A-386. CHF₂ CH₃5-OCH₃ CN H A-387. CHF₂ OCH₃ 3-F CN H A-388. CHF₂ OCH₃ 3-CH₃ CN H A-389.CHF₂ OCH₃ 3-OCH₃ CN H A-390. CHF₂ OCH₃ 5-F CN H A-391. CHF₂ OCH₃ 5-CH₃CN H A-392. CHF₂ OCH₃ 5-OCH₃ CN H A-393. CHF₂ CN 3-F CN H A-394. CHF₂ CN3-CH₃ CN H A-395. CHF₂ CN 3-OCH₃ CN H A-396. CHF₂ CN 5-F CN H A-397.CHF₂ CN 5-CH₃ CN H A-398. CHF₂ CN 5-OCH₃ CN H A-399. CHF₂ CH₂F 3-F CN HA-400. CHF₂ CH₂F 3-CH₃ CN H A-401. CHF₂ CH₂F 3-OCH₃ CN H A-402. CHF₂CH₂F 5-F CN H A-403. CHF₂ CH₂F 5-CH₃ CN H A-404. CHF₂ CH₂F 5-OCH₃ CN HA-405. CHF₂ CHF₂ 3-F CN H A-406. CHF₂ CHF₂ 3-CH₃ CN H A-407. CHF₂ CHF₂3-OCH₃ CN H A-408. CHF₂ CHF₂ 5-F CN H A-409. CHF₂ CHF₂ 5-CH₃ CN H A-410.CHF₂ CHF₂ 5-OCH₃ CN H A-411. CHF₂ CF₃ 3-F CN H A-412. CHF₂ CF₃ 3-CH₃ CNH A-413. CHF₂ CF₃ 3-OCH₃ CN H A-414. CHF₂ CF₃ 5-F CN H A-415. CHF₂ CF₃5-CH₃ CN H A-416. CHF₂ CF₃ 5-OCH₃ CN H A-417. CHF₂ OCH₂F 3-F CN H A-418.CHF₂ OCH₂F 3-CH₃ CN H A-419. CHF₂ OCH₂F 3-OCH₃ CN H A-420. CHF₂ OCH₂F5-F CN H A-421. CHF₂ OCH₂F 5-CH₃ CN H A-422. CHF₂ OCH₂F 5-OCH₃ CN HA-423. CHF₂ OCHF₂ 3-F CN H A-424. CHF₂ OCHF₂ 3-CH₃ CN H A-425. CHF₂OCHF₂ 3-OCH₃ CN H A-426. CHF₂ OCHF₂ 5-F CN H A-427. CHF₂ OCHF₂ 5-CH₃ CNH A-428. CHF₂ OCHF₂ 5-OCH₃ CN H A-429. CHF₂ OCF₃ 3-F CN H A-430. CHF₂OCF₃ 3-CH₃ CN H A-431. CHF₂ OCF₃ 3-OCH₃ CN H A-432. CHF₂ OCF₃ 5-F CN HA-433. CHF₂ OCF₃ 5-CH₃ CN H A-434. CHF₂ OCF₃ 5-OCH₃ CN H A-435. CF₃ F3-F CN H A-436. CF₃ F 3-CH₃ CN H A-437. CF₃ F 3-OCH₃ CN H A-438. CF₃ F5-F CN H A-439. CF₃ F 5-CH₃ CN H A-440. CF₃ F 5-OCH₃ CN H A-441. CF₃ CH₃3-F CN H A-442. CF₃ CH₃ 3-CH₃ CN H A-443. CF₃ CH₃ 3-OCH₃ CN H A-444. CF₃CH₃ 5-F CN H A-445. CF₃ CH₃ 5-CH₃ CN H A-446. CF₃ CH₃ 5-OCH₃ CN H A-447.CF₃ OCH₃ 3-F CN H A-448. CF₃ OCH₃ 3-CH₃ CN H A-449. CF₃ OCH₃ 3-OCH₃ CN HA-450. CF₃ OCH₃ 5-F CN H A-451. CF₃ OCH₃ 5-CH₃ CN H A-452. CF₃ OCH₃5-OCH₃ CN H A-453. CF₃ CN 3-F CN H A-454. CF₃ CN 3-CH₃ CN H A-455. CF₃CN 3-OCH₃ CN H A-456. CF₃ CN 5-F CN H A-457. CF₃ CN 5-CH₃ CN H A-458.CF₃ CN 5-OCH₃ CN H A-459. CF₃ CH₂F 3-F CN H A-460. CF₃ CH₂F 3-CH₃ CN HA-461. CF₃ CH₂F 3-OCH₃ CN H A-462. CF₃ CH₂F 5-F CN H A-463. CF₃ CH₂F5-CH₃ CN H A-464. CF₃ CH₂F 5-OCH₃ CN H A-465. CF₃ CHF₂ 3-F CN H A-466.CF₃ CHF₂ 3-CH₃ CN H A-467. CF₃ CHF₂ 3-OCH₃ CN H A-468. CF₃ CHF₂ 5-F CN HA-469. CF₃ CHF₂ 5-CH₃ CN H A-470. CF₃ CHF₂ 5-OCH₃ CN H A-471. CF₃ CF₃3-F CN H A-472. CF₃ CF₃ 3-CH₃ CN H A-473. CF₃ CF₃ 3-OCH₃ CN H A-474. CF₃CF₃ 5-F CN H A-475. CF₃ CF₃ 5-CH₃ CN H A-476. CF₃ CF₃ 5-OCH₃ CN H A-477.CF₃ OCH₂F 3-F CN H A-478. CF₃ OCH₂F 3-CH₃ CN H A-479. CF₃ OCH₂F 3-OCH₃CN H A-480. CF₃ OCH₂F 5-F CN H A-481. CF₃ OCH₂F 5-CH₃ CN H A-482. CF₃OCH₂F 5-OCH₃ CN H A-483. CF₃ OCHF₂ 3-F CN H A-484. CF₃ OCHF₂ 3-CH₃ CN HA-485. CF₃ OCHF₂ 3-OCH₃ CN H A-486. CF₃ OCHF₂ 5-F CN H A-487. CF₃ OCHF₂5-CH₃ CN H A-488. CF₃ OCHF₂ 5-OCH₃ CN H A-489. CF₃ OCF₃ 3-F CN H A-490.CF₃ OCF₃ 3-CH₃ CN H A-491. CF₃ OCF₃ 3-OCH₃ CN H A-492. CF₃ OCF₃ 5-F CN HA-493. CF₃ OCF₃ 5-CH₃ CN H A-494. CF₃ OCF₃ 5-OCH₃ CN H A-495. OCH₂F F3-F CN H A-496. OCH₂F F 3-CH₃ CN H A-497. OCH₂F F 3-OCH₃ CN H A-498.OCH₂F F 5-F CN H A-499. OCH₂F F 5-CH₃ CN H A-500. OCH₂F F 5-OCH₃ CN HA-501. OCH₂F CH₃ 3-F CN H A-502. OCH₂F CH₃ 3-CH₃ CN H A-503. OCH₂F CH₃3-OCH₃ CN H A-504. OCH₂F CH₃ 5-F CN H A-505. OCH₂F CH₃ 5-CH₃ CN H A-506.OCH₂F CH₃ 5-OCH₃ CN H A-507. OCH₂F OCH₃ 3-F CN H A-508. OCH₂F OCH₃ 3-CH₃CN H A-509. OCH₂F OCH₃ 3-OCH₃ CN H A-510. OCH₂F OCH₃ 5-F CN H A-511.OCH₂F OCH₃ 5-CH₃ CN H A-512. OCH₂F OCH₃ 5-OCH₃ CN H A-513. OCH₂F CN 3-FCN H A-514. OCH₂F CN 3-CH₃ CN H A-515. OCH₂F CN 3-OCH₃ CN H A-516. OCH₂FCN 5-F CN H A-517. OCH₂F CN 5-CH₃ CN H A-518. OCH₂F CN 5-OCH₃ CN HA-519. OCH₂F CH₂F 3-F CN H A-520. OCH₂F CH₂F 3-CH₃ CN H A-521. OCH₂FCH₂F 3-OCH₃ CN H A-522. OCH₂F CH₂F 5-F CN H A-523. OCH₂F CH₂F 5-CH₃ CN HA-524. OCH₂F CH₂F 5-OCH₃ CN H A-525. OCH₂F CHF₂ 3-F CN H A-526. OCH₂FCHF₂ 3-CH₃ CN H A-527. OCH₂F CHF₂ 3-OCH₃ CN H A-528. OCH₂F CHF₂ 5-F CN HA-529. OCH₂F CHF₂ 5-CH₃ CN H A-530. OCH₂F CHF₂ 5-OCH₃ CN H A-531. OCH₂FCF₃ 3-F CN H A-532. OCH₂F CF₃ 3-CH₃ CN H A-533. OCH₂F CF₃ 3-OCH₃ CN HA-534. OCH₂F CF₃ 5-F CN H A-535. OCH₂F CF₃ 5-CH₃ CN H A-536. OCH₂F CF₃5-OCH₃ CN H A-537. OCH₂F OCH₂F 3-F CN H A-538. OCH₂F OCH₂F 3-CH₃ CN HA-539. OCH₂F OCH₂F 3-OCH₃ CN H A-540. OCH₂F OCH₂F 5-F CN H A-541. OCH₂FOCH₂F 5-CH₃ CN H A-542. OCH₂F OCH₂F 5-OCH₃ CN H A-543. OCH₂F OCHF₂ 3-FCN H A-544. OCH₂F OCHF₂ 3-CH₃ CN H A-545. OCH₂F OCHF₂ 3-OCH₃ CN H A-546.OCH₂F OCHF₂ 5-F CN H A-547. OCH₂F OCHF₂ 5-CH₃ CN H A-548. OCH₂F OCHF₂5-OCH₃ CN H A-549. OCH₂F OCF₃ 3-F CN H A-550. OCH₂F OCF₃ 3-CH₃ CN HA-551. OCH₂F OCF₃ 3-OCH₃ CN H A-552. OCH₂F OCF₃ 5-F CN H A-553. OCH₂FOCF₃ 5-CH₃ CN H A-554. OCH₂F OCF₃ 5-OCH₃ CN H A-555. OCHF₂ F 3-F CN HA-556. OCHF₂ F 3-CH₃ CN H A-557. OCHF₂ F 3-OCH₃ CN H A-558. OCHF₂ F 5-FCN H A-559. OCHF₂ F 5-CH₃ CN H A-560. OCHF₂ F 5-OCH₃ CN H A-561. OCHF₂CH₃ 3-F CN H A-562. OCHF₂ CH₃ 3-CH₃ CN H A-563. OCHF₂ CH₃ 3-OCH₃ CN HA-564. OCHF₂ CH₃ 5-F CN H A-565. OCHF₂ CH₃ 5-CH₃ CN H A-566. OCHF₂ CH₃5-OCH₃ CN H A-567. OCHF₂ OCH₃ 3-F CN H A-568. OCHF₂ OCH₃ 3-CH₃ CN HA-569. OCHF₂ OCH₃ 3-OCH₃ CN H A-570. OCHF₂ OCH₃ 5-F CN H A-571. OCHF₂OCH₃ 5-CH₃ CN H A-572. OCHF₂ OCH₃ 5-OCH₃ CN H A-573. OCHF₂ CN 3-F CN HA-574. OCHF₂ CN 3-CH₃ CN H A-575. OCHF₂ CN 3-OCH₃ CN H A-576. OCHF₂ CN5-F CN H A-577. OCHF₂ CN 5-CH₃ CN H A-578. OCHF₂ CN 5-OCH₃ CN H A-579.OCHF₂ CH₂F 3-F CN H A-580. OCHF₂ CH₂F 3-CH₃ CN H A-581. OCHF₂ CH₂F3-OCH₃ CN H A-582. OCHF₂ CH₂F 5-F CN H A-583. OCHF₂ CH₂F 5-CH₃ CN HA-584. OCHF₂ CH₂F 5-OCH₃ CN H A-585. OCHF₂ CHF₂ 3-F CN H A-586. OCHF₂CHF₂ 3-CH₃ CN H A-587. OCHF₂ CHF₂ 3-OCH₃ CN H A-588. OCHF₂ CHF₂ 5-F CN HA-589. OCHF₂ CHF₂ 5-CH₃ CN H A-590. OCHF₂ CHF₂ 5-OCH₃ CN H A-591. OCHF₂CF₃ 3-F CN H A-592. OCHF₂ CF₃ 3-CH₃ CN H A-593. OCHF₂ CF₃ 3-OCH₃ CN HA-594. OCHF₂ CF₃ 5-F CN H A-595. OCHF₂ CF₃ 5-CH₃ CN H A-596. OCHF₂ CF₃5-OCH₃ CN H A-597. OCHF₂ OCH₂F 3-F CN H A-598. OCHF₂ OCH₂F 3-CH₃ CN HA-599. OCHF₂ OCH₂F 3-OCH₃ CN H A-600. OCHF₂ OCH₂F 5-F CN H A-601. OCHF₂OCH₂F 5-CH₃ CN H A-602. OCHF₂ OCH₂F 5-OCH₃ CN H A-603. OCHF₂ OCHF₂ 3-FCN H A-604. OCHF₂ OCHF₂ 3-CH₃ CN H A-605. OCHF₂ OCHF₂ 3-OCH₃ CN H A-606.OCHF₂ OCHF₂ 5-F CN H A-607. OCHF₂ OCHF₂ 5-CH₃ CN H A-608. OCHF₂ OCHF₂5-OCH₃ CN H A-609. OCHF₂ OCF₃ 3-F CN H A-610. OCHF₂ OCF₃ 3-CH₃ CN HA-611. OCHF₂ OCF₃ 3-OCH₃ CN H A-612. OCHF₂ OCF₃ 5-F CN H A-613. OCHF₂OCF₃ 5-CH₃ CN H A-614. OCHF₂ OCF₃ 5-OCH₃ CN H A-615. OCF₃ F 3-F CN HA-616. OCF₃ F 3-CH₃ CN H A-617. OCF₃ F 3-OCH₃ CN H A-618. OCF₃ F 5-F CNH A-619. OCF₃ F 5-CH₃ CN H A-620. OCF₃ F 5-OCH₃ CN H A-621. OCF₃ CH₃ 3-FCN H A-622. OCF₃ CH₃ 3-CH₃ CN H A-623. OCF₃ CH₃ 3-OCH₃ CN H A-624. OCF₃CH₃ 5-F CN H A-625. OCF₃ CH₃ 5-CH₃ CN H A-626. OCF₃ CH₃ 5-OCH₃ CN HA-627. OCF₃ OCH₃ 3-F CN H A-628. OCF₃ OCH₃ 3-CH₃ CN H A-629. OCF₃ OCH₃3-OCH₃ CN H A-630. OCF₃ OCH₃ 5-F CN H A-631. OCF₃ OCH₃ 5-CH₃ CN H A-632.OCF₃ OCH₃ 5-OCH₃ CN H A-633. OCF₃ CN 3-F CN H A-634. OCF₃ CN 3-CH₃ CN HA-635. OCF₃ CN 3-OCH₃ CN H A-636. OCF₃ CN 5-F CN H A-637. OCF₃ CN 5-CH₃CN H A-638. OCF₃ CN 5-OCH₃ CN H A-639. OCF₃ CH₂F 3-F CN H A-640. OCF₃CH₂F 3-CH₃ CN H A-641. OCF₃ CH₂F 3-OCH₃ CN H A-642. OCF₃ CH₂F 5-F CN HA-643. OCF₃ CH₂F 5-CH₃ CN H A-644. OCF₃ CH₂F 5-OCH₃ CN H A-645. OCF₃CHF₂ 3-F CN H A-646. OCF₃ CHF₂ 3-CH₃ CN H A-647. OCF₃ CHF₂ 3-OCH₃ CN HA-648. OCF₃ CHF₂ 5-F CN H A-649. OCF₃ CHF₂ 5-CH₃ CN H A-650. OCF₃ CHF₂5-OCH₃ CN H A-651. OCF₃ CF₃ 3-F CN H A-652. OCF₃ CF₃ 3-CH₃ CN H A-653.OCF₃ CF₃ 3-OCH₃ CN H A-654. OCF₃ CF₃ 5-F CN H A-655. OCF₃ CF₃ 5-CH₃ CN HA-656. OCF₃ CF₃ 5-OCH₃ CN H A-657. OCF₃ OCH₂F 3-F CN H A-658. OCF₃ OCH₂F3-CH₃ CN H A-659. OCF₃ OCH₂F 3-OCH₃ CN H A-660. OCF₃ OCH₂F 5-F CN HA-661. OCF₃ OCH₂F 5-CH₃ CN H A-662. OCF₃ OCH₂F 5-OCH₃ CN H A-663. OCF₃OCHF₂ 3-F CN H A-664. OCF₃ OCHF₂ 3-CH₃ CN H A-665. OCF₃ OCHF₂ 3-OCH₃ CNH A-666. OCF₃ OCHF₂ 5-F CN H A-667. OCF₃ OCHF₂ 5-CH₃ CN H A-668. OCF₃OCHF₂ 5-OCH₃ CN H A-669. OCF₃ OCF₃ 3-F CN H A-670. OCF₃ OCF₃ 3-CH₃ CN HA-671. OCF₃ OCF₃ 3-OCH₃ CN H A-672. OCF₃ OCF₃ 5-F CN H A-673. OCF₃ OCF₃5-CH₃ CN H A-674. OCF₃ OCF₃ 5-OCH₃ CN H A-675. H H H F H A-676. F H H FH A-677. CH₃ H H F H A-678. OCH₃ H H F H A-679. CH₂F H H F H A-680. CHF₂H H F H A-681. CF₃ H H F H A-682. OCH₂F H H F H A-683. OCHF₂ H H F HA-684. OCF₃ H H F H A-685. H F H F H A-686. H CH₃ H F H A-687. H OCH₃ HF H A-688. H CN H F H A-689. H CH₂F H F H A-690. H CHF₂ H F H A-691. HCF₃ H F H A-692. H OCH₂F H F H A-693. H OCHF₂ H F H A-694. H OCF₃ H F HA-695. H H 3-F F H A-696. H H 3-CH₃ F H A-697. H H 3-OCH₃ F H A-698. H H5-F F H A-699. H H 5-CH₃ F H A-700. H H 5-OCH₃ F H A-701. F F H F HA-702. F CH₃ H F H A-703. F OCH₃ H F H A-704. F CN H F H A-705. F CH₂F HF H A-706. F CHF₂ H F H A-707. F CF₃ H F H A-708. F OCH₂F H F H A-709. FOCHF₂ H F H A-710. F OCF₃ H F H A-711. F H 3-F F H A-712. F H 3-CH₃ F HA-713. F H 3-OCH₃ F H A-714. F H 5-F F H A-715. F H 5-CH₃ F H A-716. F H5-OCH₃ F H A-717. CH₃ F H F H A-718. CH₃ CH₃ H F H A-719. CH₃ OCH₃ H F HA-720. CH₃ CN H F H A-721. CH₃ CH₂F H F H A-722. CH₃ CHF₂ H F H A-723.CH₃ CF₃ H F H A-724. CH₃ OCH₂F H F H A-725. CH₃ OCHF₂ H F H A-726. CH₃OCF₃ H F H A-727. CH₃ H 3-F F H A-728. CH₃ H 3-CH₃ F H A-729. CH₃ H3-OCH₃ F H A-730. CH₃ H 5-F F H A-731. CH₃ H 5-CH₃ F H A-732. CH₃ H5-OCH₃ F H A-733. OCH₃ F H F H A-734. OCH₃ CH₃ H F H A-735. OCH₃ OCH₃ HF H A-736. OCH₃ CN H F H A-737. OCH₃ CH₂F H F H A-738. OCH₃ CHF₂ H F HA-739. OCH₃ CF₃ H F H A-740. OCH₃ OCH₂F H F H A-741. OCH₃ OCHF₂ H F HA-742. OCH₃ OCF₃ H F H A-743. OCH₃ H 3-F F H A-744. OCH₃ H 3-CH₃ F HA-745. OCH₃ H 3-OCH₃ F H A-746. OCH₃ H 5-F F H A-747. OCH₃ H 5-CH₃ F HA-748. OCH₃ H 5-OCH₃ F H A-749. H F 3-F F H A-750. H F 3-CH₃ F H A-751.H F 3-OCH₃ F H A-752. H F 5-F F H A-753. H F 5-CH₃ F H A-754. H F 5-OCH₃F H A-755. H CH₃ 3-F F H A-756. H CH₃ 3-CH₃ F H A-757. H CH₃ 3-OCH₃ F HA-758. H CH₃ 5-F F H A-759. H CH₃ 5-CH₃ F H A-760. H CH₃ 5-OCH₃ F HA-761. H OCH₃ 3-F F H A-762. H OCH₃ 3-CH₃ F H A-763. H OCH₃ 3-OCH₃ F HA-764. H OCH₃ 5-F F H A-765. H OCH₃ 5-CH₃ F H A-766. H OCH₃ 5-OCH₃ F HA-767. H CN 3-F F H A-768. H CN 3-CH₃ F H A-769. H CN 3-OCH₃ F H A-770.H CN 5-F F H A-771. H CN 5-CH₃ F H A-772. H CN 5-OCH₃ F H A-773. H CH₂F3-F F H A-774. H CH₂F 3-CH₃ F H A-775. H CH₂F 3-OCH₃ F H A-776. H CH₂F5-F F H A-777. H CH₂F 5-CH₃ F H A-778. H CH₂F 5-OCH₃ F H A-779. H CHF₂3-F F H A-780. H CHF₂ 3-CH₃ F H A-781. H CHF₂ 3-OCH₃ F H A-782. H CHF₂5-F F H A-783. H CHF₂ 5-CH₃ F H A-784. H CHF₂ 5-OCH₃ F H A-785. H CF₃3-F F H A-786. H CF₃ 3-CH₃ F H A-787. H CF₃ 3-OCH₃ F H A-788. H CF₃ 5-FF H A-789. H CF₃ 5-CH₃ F H A-790. H CF₃ 5-OCH₃ F H A-791. H OCH₂F 3-F FH A-792. H OCH₂F 3-CH₃ F H A-793. H OCH₂F 3-OCH₃ F H A-794. H OCH₂F 5-FF H A-795. H OCH₂F 5-CH₃ F H A-796. H OCH₂F 5-OCH₃ F H A-797. H OCHF₂3-F F H A-798. H OCHF₂ 3-CH₃ F H A-799. H OCHF₂ 3-OCH₃ F H A-800. HOCHF₂ 5-F F H A-801. H OCHF₂ 5-CH₃ F H A-802. H OCHF₂ 5-OCH₃ F H A-803.H OCF₃ 3-F F H A-804. H OCF₃ 3-CH₃ F H A-805. H OCF₃ 3-OCH₃ F H A-806. HOCF₃ 5-F F H A-807. H OCF₃ 5-CH₃ F H A-808. H OCF₃ 5-OCH₃ F H A-809. F F3-F F H A-810. F F 3-CH₃ F H A-811. F F 3-OCH₃ F H A-812. F F 5-F F HA-813. F F 5-CH₃ F H A-814. F F 5-OCH₃ F H A-815. F CH₃ 3-F F H A-816. FCH₃ 3-CH₃ F H A-817. F CH₃ 3-OCH₃ F H A-818. F CH₃ 5-F F H A-819. F CH₃5-CH₃ F H A-820. F CH₃ 5-OCH₃ F H A-821. F OCH₃ 3-F F H A-822. F OCH₃3-CH₃ F H A-823. F OCH₃ 3-OCH₃ F H A-824. F OCH₃ 5-F F H A-825. F OCH₃5-CH₃ F H A-826. F OCH₃ 5-OCH₃ F H A-827. F CN 3-F F H A-828. F CN 3-CH₃F H A-829. F CN 3-OCH₃ F H A-830. F CN 5-F F H A-831. F CN 5-CH₃ F HA-832. F CN 5-OCH₃ F H A-833. F CH₂F 3-F F H A-834. F CH₂F 3-CH₃ F HA-835. F CH₂F 3-OCH₃ F H A-836. F CH₂F 5-F F H A-837. F CH₂F 5-CH₃ F HA-838. F CH₂F 5-OCH₃ F H A-839. F CHF₂ 3-F F H A-840. F CHF₂ 3-CH₃ F HA-841. F CHF₂ 3-OCH₃ F H A-842. F CHF₂ 5-F F H A-843. F CHF₂ 5-CH₃ F HA-844. F CHF₂ 5-OCH₃ F H A-845. F CF₃ 3-F F H A-846. F CF₃ 3-CH₃ F HA-847. F CF₃ 3-OCH₃ F H A-848. F CF₃ 5-F F H A-849. F CF₃ 5-CH₃ F HA-850. F CF₃ 5-OCH₃ F H A-851. F OCH₂F 3-F F H A-852. F OCH₂F 3-CH₃ F HA-853. F OCH₂F 3-OCH₃ F H A-854. F OCH₂F 5-F F H A-855. F OCH₂F 5-CH₃ FH A-856. F OCH₂F 5-OCH₃ F H A-857. F OCHF₂ 3-F F H A-858. F OCHF₂ 3-CH₃F H A-859. F OCHF₂ 3-OCH₃ F H A-860. F OCHF₂ 5-F F H A-861. F OCHF₂5-CH₃ F H A-862. F OCHF₂ 5-OCH₃ F H A-863. F OCF₃ 3-F F H A-864. F OCF₃3-CH₃ F H A-865. F OCF₃ 3-OCH₃ F H A-866. F OCF₃ 5-F F H A-867. F OCF₃5-CH₃ F H A-868. F OCF₃ 5-OCH₃ F H A-869. CH₃ F 3-F F H A-870. CH₃ F3-CH₃ F H A-871. CH₃ F 3-OCH₃ F H A-872. CH₃ F 5-F F H A-873. CH₃ F5-CH₃ F H A-874. CH₃ F 5-OCH₃ F H A-875. CH₃ CH₃ 3-F F H A-876. CH₃ CH₃3-CH₃ F H A-877. CH₃ CH₃ 3-OCH₃ F H A-878. CH₃ CH₃ 5-F F H A-879. CH₃CH₃ 5-CH₃ F H A-880. CH₃ CH₃ 5-OCH₃ F H A-881. CH₃ OCH₃ 3-F F H A-882.CH₃ OCH₃ 3-CH₃ F H A-883. CH₃ OCH₃ 3-OCH₃ F H A-884. CH₃ OCH₃ 5-F F HA-885. CH₃ OCH₃ 5-CH₃ F H A-886. CH₃ OCH₃ 5-OCH₃ F H A-887. CH₃ CN 3-F FH A-888. CH₃ CN 3-CH₃ F H A-889. CH₃ CN 3-OCH₃ F H A-890. CH₃ CN 5-F F HA-891. CH₃ CN 5-CH₃ F H A-892. CH₃ CN 5-OCH₃ F H A-893. CH₃ CH₂F 3-F F HA-894. CH₃ CH₂F 3-CH₃ F H A-895. CH₃ CH₂F 3-OCH₃ F H A-896. CH₃ CH₂F 5-FF H A-897. CH₃ CH₂F 5-CH₃ F H A-898. CH₃ CH₂F 5-OCH₃ F H A-899. CH₃ CHF₂3-F F H A-900. CH₃ CHF₂ 3-CH₃ F H A-901. CH₃ CHF₂ 3-OCH₃ F H A-902. CH₃CHF₂ 5-F F H A-903. CH₃ CHF₂ 5-CH₃ F H A-904. CH₃ CHF₂ 5-OCH₃ F H A-905.CH₃ CF₃ 3-F F H A-906. CH₃ CF₃ 3-CH₃ F H A-907. CH₃ CF₃ 3-OCH₃ F HA-908. CH₃ CF₃ 5-F F H A-909. CH₃ CF₃ 5-CH₃ F H A-910. CH₃ CF₃ 5-OCH₃ FH A-911. CH₃ OCH₂F 3-F F H A-912. CH₃ OCH₂F 3-CH₃ F H A-913. CH₃ OCH₂F3-OCH₃ F H A-914. CH₃ OCH₂F 5-F F H A-915. CH₃ OCH₂F 5-CH₃ F H A-916.CH₃ OCH₂F 5-OCH₃ F H A-917. CH₃ OCHF₂ 3-F F H A-918. CH₃ OCHF₂ 3-CH₃ F HA-919. CH₃ OCHF₂ 3-OCH₃ F H A-920. CH₃ OCHF₂ 5-F F H A-921. CH₃ OCHF₂5-CH₃ F H A-922. CH₃ OCHF₂ 5-OCH₃ F H A-923. CH₃ OCF₃ 3-F F H A-924. CH₃OCF₃ 3-CH₃ F H A-925. CH₃ OCF₃ 3-OCH₃ F H A-926. CH₃ OCF₃ 5-F F H A-927.CH₃ OCF₃ 5-CH₃ F H A-928. CH₃ OCF₃ 5-OCH₃ F H A-929. OCH₃ F 3-F F HA-930. OCH₃ F 3-CH₃ F H A-931. OCH₃ F 3-OCH₃ F H A-932. OCH₃ F 5-F F HA-933. OCH₃ F 5-CH₃ F H A-934. OCH₃ F 5-OCH₃ F H A-935. OCH₃ CH₃ 3-F F HA-936. OCH₃ CH₃ 3-CH₃ F H A-937. OCH₃ CH₃ 3-OCH₃ F H A-938. OCH₃ CH₃ 5-FF H A-939. OCH₃ CH₃ 5-CH₃ F H A-940. OCH₃ CH₃ 5-OCH₃ F H A-941. OCH₃OCH₃ 3-F F H A-942. OCH₃ OCH₃ 3-CH₃ F H A-943. OCH₃ OCH₃ 3-OCH₃ F HA-944. OCH₃ OCH₃ 5-F F H A-945. OCH₃ OCH₃ 5-CH₃ F H A-946. OCH₃ OCH₃5-OCH₃ F H A-947. OCH₃ CN 3-F F H A-948. OCH₃ CN 3-CH₃ F H A-949. OCH₃CN 3-OCH₃ F H A-950. OCH₃ CN 5-F F H A-951. OCH₃ CN 5-CH₃ F H A-952.OCH₃ CN 5-OCH₃ F H A-953. OCH₃ CH₂F 3-F F H A-954. OCH₃ CH₂F 3-CH₃ F HA-955. OCH₃ CH₂F 3-OCH₃ F H A-956. OCH₃ CH₂F 5-F F H A-957. OCH₃ CH₂F5-CH₃ F H A-958. OCH₃ CH₂F 5-OCH₃ F H A-959. OCH₃ CHF₂ 3-F F H A-960.OCH₃ CHF₂ 3-CH₃ F H A-961. OCH₃ CHF₂ 3-OCH₃ F H A-962. OCH₃ CHF₂ 5-F F HA-963. OCH₃ CHF₂ 5-CH₃ F H A-964. OCH₃ CHF₂ 5-OCH₃ F H A-965. OCH₃ CF₃3-F F H A-966. OCH₃ CF₃ 3-CH₃ F H A-967. OCH₃ CF₃ 3-OCH₃ F H A-968. OCH₃CF₃ 5-F F H A-969. OCH₃ CF₃ 5-CH₃ F H A-970. OCH₃ CF₃ 5-OCH₃ F H A-971.OCH₃ OCH₂F 3-F F H A-972. OCH₃ OCH₂F 3-CH₃ F H A-973. OCH₃ OCH₂F 3-OCH₃F H A-974. OCH₃ OCH₂F 5-F F H A-975. OCH₃ OCH₂F 5-CH₃ F H A-976. OCH₃OCH₂F 5-OCH₃ F H A-977. OCH₃ OCHF₂ 3-F F H A-978. OCH₃ OCHF₂ 3-CH₃ F HA-979. OCH₃ OCHF₂ 3-OCH₃ F H A-980. OCH₃ OCHF₂ 5-F F H A-981. OCH₃ OCHF₂5-CH₃ F H A-982. OCH₃ OCHF₂ 5-OCH₃ F H A-983. OCH₃ OCF₃ 3-F F H A-984.OCH₃ OCF₃ 3-CH₃ F H A-985. OCH₃ OCF₃ 3-OCH₃ F H A-986. OCH₃ OCF₃ 5-F F HA-987. OCH₃ OCF₃ 5-CH₃ F H A-988. OCH₃ OCF₃ 5-OCH₃ F H A-989. CH₂F F 3-FF H A-990. CH₂F F 3-CH₃ F H A-991. CH₂F F 3-OCH₃ F H A-992. CH₂F F 5-F FH A-993. CH₂F F 5-CH₃ F H A-994. CH₂F F 5-OCH₃ F H A-995. CH₂F CH₃ 3-F FH A-996. CH₂F CH₃ 3-CH₃ F H A-997. CH₂F CH₃ 3-OCH₃ F H A-998. CH₂F CH₃5-F F H A-999. CH₂F CH₃ 5-CH₃ F H A-1000. CH₂F CH₃ 5-OCH₃ F H A-1001.CH₂F OCH₃ 3-F F H A-1002. CH₂F OCH₃ 3-CH₃ F H A-1003. CH₂F OCH₃ 3-OCH₃ FH A-1004. CH₂F OCH₃ 5-F F H A-1005. CH₂F OCH₃ 5-CH₃ F H A-1006. CH₂FOCH₃ 5-OCH₃ F H A-1007. CH₂F CN 3-F F H A-1008. CH₂F CN 3-CH₃ F HA-1009. CH₂F CN 3-OCH₃ F H A-1010. CH₂F CN 5-F F H A-1011. CH₂F CN 5-CH₃F H A-1012. CH₂F CN 5-OCH₃ F H A-1013. CH₂F CH₂F 3-F F H A-1014. CH₂FCH₂F 3-CH₃ F H A-1015. CH₂F CH₂F 3-OCH₃ F H A-1016. CH₂F CH₂F 5-F F HA-1017. CH₂F CH₂F 5-CH₃ F H A-1018. CH₂F CH₂F 5-OCH₃ F H A-1019. CH₂FCHF₂ 3-F F H A-1020. CH₂F CHF₂ 3-CH₃ F H A-1021. CH₂F CHF₂ 3-OCH₃ F HA-1022. CH₂F CHF₂ 5-F F H A-1023. CH₂F CHF₂ 5-CH₃ F H A-1024. CH₂F CHF₂5-OCH₃ F H A-1025. CH₂F CF₃ 3-F F H A-1026. CH₂F CF₃ 3-CH₃ F H A-1027.CH₂F CF₃ 3-OCH₃ F H A-1028. CH₂F CF₃ 5-F F H A-1029. CH₂F CF₃ 5-CH₃ F HA-1030. CH₂F CF₃ 5-OCH₃ F H A-1031. CH₂F OCH₂F 3-F F H A-1032. CH₂FOCH₂F 3-CH₃ F H A-1033. CH₂F OCH₂F 3-OCH₃ F H A-1034. CH₂F OCH₂F 5-F F HA-1035. CH₂F OCH₂F 5-CH₃ F H A-1036. CH₂F OCH₂F 5-OCH₃ F H A-1037. CH₂FOCHF₂ 3-F F H A-1038. CH₂F OCHF₂ 3-CH₃ F H A-1039. CH₂F OCHF₂ 3-OCH₃ F HA-1040. CH₂F OCHF₂ 5-F F H A-1041. CH₂F OCHF₂ 5-CH₃ F H A-1042. CH₂FOCHF₂ 5-OCH₃ F H A-1043. CH₂F OCF₃ 3-F F H A-1044. CH₂F OCF₃ 3-CH₃ F HA-1045. CH₂F OCF₃ 3-OCH₃ F H A-1046. CH₂F OCF₃ 5-F F H A-1047. CH₂F OCF₃5-CH₃ F H A-1048. CH₂F OCF₃ 5-OCH₃ F H A-1049. CHF₂ F 3-F F H A-1050.CHF₂ F 3-CH₃ F H A-1051. CHF₂ F 3-OCH₃ F H A-1052. CHF₂ F 5-F F HA-1053. CHF₂ F 5-CH₃ F H A-1054. CHF₂ F 5-OCH₃ F H A-1055. CHF₂ CH₃ 3-FF H A-1056. CHF₂ CH₃ 3-CH₃ F H A-1057. CHF₂ CH₃ 3-OCH₃ F H A-1058. CHF₂CH₃ 5-F F H A-1059. CHF₂ CH₃ 5-CH₃ F H A-1060. CHF₂ CH₃ 5-OCH₃ F HA-1061. CHF₂ OCH₃ 3-F F H A-1062. CHF₂ OCH₃ 3-CH₃ F H A-1063. CHF₂ OCH₃3-OCH₃ F H A-1064. CHF₂ OCH₃ 5-F F H A-1065. CHF₂ OCH₃ 5-CH₃ F H A-1066.CHF₂ OCH₃ 5-OCH₃ F H A-1067. CHF₂ CN 3-F F H A-1068. CHF₂ CN 3-CH₃ F HA-1069. CHF₂ CN 3-OCH₃ F H A-1070. CHF₂ CN 5-F F H A-1071. CHF₂ CN 5-CH₃F H A-1072. CHF₂ CN 5-OCH₃ F H A-1073. CHF₂ CH₂F 3-F F H A-1074. CHF₂CH₂F 3-CH₃ F H A-1075. CHF₂ CH₂F 3-OCH₃ F H A-1076. CHF₂ CH₂F 5-F F HA-1077. CHF₂ CH₂F 5-CH₃ F H A-1078. CHF₂ CH₂F 5-OCH₃ F H A-1079. CHF₂CHF₂ 3-F F H A-1080. CHF₂ CHF₂ 3-CH₃ F H A-1081. CHF₂ CHF₂ 3-OCH₃ F HA-1082. CHF₂ CHF₂ 5-F F H A-1083. CHF₂ CHF₂ 5-CH₃ F H A-1084. CHF₂ CHF₂5-OCH₃ F H A-1085. CHF₂ CF₃ 3-F F H A-1086. CHF₂ CF₃ 3-CH₃ F H A-1087.CHF₂ CF₃ 3-OCH₃ F H A-1088. CHF₂ CF₃ 5-F F H A-1089. CHF₂ CF₃ 5-CH₃ F HA-1090. CHF₂ CF₃ 5-OCH₃ F H A-1091. CHF₂ OCH₂F 3-F F H A-1092. CHF₂OCH₂F 3-CH₃ F H A-1093. CHF₂ OCH₂F 3-OCH₃ F H A-1094. CHF₂ OCH₂F 5-F F HA-1095. CHF₂ OCH₂F 5-CH₃ F H A-1096. CHF₂ OCH₂F 5-OCH₃ F H A-1097. CHF₂OCHF₂ 3-F F H A-1098. CHF₂ OCHF₂ 3-CH₃ F H A-1099. CHF₂ OCHF₂ 3-OCH₃ F HA-1100. CHF₂ OCHF₂ 5-F F H A-1101. CHF₂ OCHF₂ 5-CH₃ F H A-1102. CHF₂OCHF₂ 5-OCH₃ F H A-1103. CHF₂ OCF₃ 3-F F H A-1104. CHF₂ OCF₃ 3-CH₃ F HA-1105. CHF₂ OCF₃ 3-OCH₃ F H A-1106. CHF₂ OCF₃ 5-F F H A-1107. CHF₂ OCF₃5-CH₃ F H A-1108. CHF₂ OCF₃ 5-OCH₃ F H A-1109. CF₃ F 3-F F H A-1110. CF₃F 3-CH₃ F H A-1111. CF₃ F 3-OCH₃ F H A-1112. CF₃ F 5-F F H A-1113. CF₃ F5-CH₃ F H A-1114. CF₃ F 5-OCH₃ F H A-1115. CF₃ CH₃ 3-F F H A-1116. CF₃CH₃ 3-CH₃ F H A-1117. CF₃ CH₃ 3-OCH₃ F H A-1118. CF₃ CH₃ 5-F F H A-1119.CF₃ CH₃ 5-CH₃ F H A-1120. CF₃ CH₃ 5-OCH₃ F H A-1121. CF₃ OCH₃ 3-F F HA-1122. CF₃ OCH₃ 3-CH₃ F H A-1123. CF₃ OCH₃ 3-OCH₃ F H A-1124. CF₃ OCH₃5-F F H A-1125. CF₃ OCH₃ 5-CH₃ F H A-1126. CF₃ OCH₃ 5-OCH₃ F H A-1127.CF₃ CN 3-F F H A-1128. CF₃ CN 3-CH₃ F H A-1129. CF₃ CN 3-OCH₃ F HA-1130. CF₃ CN 5-F F H A-1131. CF₃ CN 5-CH₃ F H A-1132. CF₃ CN 5-OCH₃ FH A-1133. CF₃ CH₂F 3-F F H A-1134. CF₃ CH₂F 3-CH₃ F H A-1135. CF₃ CH₂F3-OCH₃ F H A-1136. CF₃ CH₂F 5-F F H A-1137. CF₃ CH₂F 5-CH₃ F H A-1138.CF₃ CH₂F 5-OCH₃ F H A-1139. CF₃ CHF₂ 3-F F H A-1140. CF₃ CHF₂ 3-CH₃ F HA-1141. CF₃ CHF₂ 3-OCH₃ F H A-1142. CF₃ CHF₂ 5-F F H A-1143. CF₃ CHF₂5-CH₃ F H A-1144. CF₃ CHF₂ 5-OCH₃ F H A-1145. CF₃ CF₃ 3-F F H A-1146.CF₃ CF₃ 3-CH₃ F H A-1147. CF₃ CF₃ 3-OCH₃ F H A-1148. CF₃ CF₃ 5-F F HA-1149. CF₃ CF₃ 5-CH₃ F H A-1150. CF₃ CF₃ 5-OCH₃ F H A-1151. CF₃ OCH₂F3-F F H A-1152. CF₃ OCH₂F 3-CH₃ F H A-1153. CF₃ OCH₂F 3-OCH₃ F H A-1154.CF₃ OCH₂F 5-F F H A-1155. CF₃ OCH₂F 5-CH₃ F H A-1156. CF₃ OCH₂F 5-OCH₃ FH A-1157. CF₃ OCHF₂ 3-F F H A-1158. CF₃ OCHF₂ 3-CH₃ F H A-1159. CF₃OCHF₂ 3-OCH₃ F H A-1160. CF₃ OCHF₂ 5-F F H A-1161. CF₃ OCHF₂ 5-CH₃ F HA-1162. CF₃ OCHF₂ 5-OCH₃ F H A-1163. CF₃ OCF₃ 3-F F H A-1164. CF₃ OCF₃3-CH₃ F H A-1165. CF₃ OCF₃ 3-OCH₃ F H A-1166. CF₃ OCF₃ 5-F F H A-1167.CF₃ OCF₃ 5-CH₃ F H A-1168. CF₃ OCF₃ 5-OCH₃ F H A-1169. OCH₂F F 3-F F HA-1170. OCH₂F F 3-CH₃ F H A-1171. OCH₂F F 3-OCH₃ F H A-1172. OCH₂F F 5-FF H A-1173. OCH₂F F 5-CH₃ F H A-1174. OCH₂F F 5-OCH₃ F H A-1175. OCH₂FCH₃ 3-F F H A-1176. OCH₂F CH₃ 3-CH₃ F H A-1177. OCH₂F CH₃ 3-OCH₃ F HA-1178. OCH₂F CH₃ 5-F F H A-1179. OCH₂F CH₃ 5-CH₃ F H A-1180. OCH₂F CH₃5-OCH₃ F H A-1181. OCH₂F OCH₃ 3-F F H A-1182. OCH₂F OCH₃ 3-CH₃ F HA-1183. OCH₂F OCH₃ 3-OCH₃ F H A-1184. OCH₂F OCH₃ 5-F F H A-1185. OCH₂FOCH₃ 5-CH₃ F H A-1186. OCH₂F OCH₃ 5-OCH₃ F H A-1187. OCH₂F CN 3-F F HA-1188. OCH₂F CN 3-CH₃ F H A-1189. OCH₂F CN 3-OCH₃ F H A-1190. OCH₂F CN5-F F H A-1191. OCH₂F CN 5-CH₃ F H A-1192. OCH₂F CN 5-OCH₃ F H A-1193.OCH₂F CH₂F 3-F F H A-1194. OCH₂F CH₂F 3-CH₃ F H A-1195. OCH₂F CH₂F3-OCH₃ F H A-1196. OCH₂F CH₂F 5-F F H A-1197. OCH₂F CH₂F 5-CH₃ F HA-1198. OCH₂F CH₂F 5-OCH₃ F H A-1199. OCH₂F CHF₂ 3-F F H A-1200. OCH₂FCHF₂ 3-CH₃ F H A-1201. OCH₂F CHF₂ 3-OCH₃ F H A-1202. OCH₂F CHF₂ 5-F F HA-1203. OCH₂F CHF₂ 5-CH₃ F H A-1204. OCH₂F CHF₂ 5-OCH₃ F H A-1205. OCH₂FCF₃ 3-F F H A-1206. OCH₂F CF₃ 3-CH₃ F H A-1207. OCH₂F CF₃ 3-OCH₃ F HA-1208. OCH₂F CF₃ 5-F F H A-1209. OCH₂F CF₃ 5-CH₃ F H A-1210. OCH₂F CF₃5-OCH₃ F H A-1211. OCH₂F OCH₂F 3-F F H A-1212. OCH₂F OCH₂F 3-CH₃ F HA-1213. OCH₂F OCH₂F 3-OCH₃ F H A-1214. OCH₂F OCH₂F 5-F F H A-1215. OCH₂FOCH₂F 5-CH₃ F H A-1216. OCH₂F OCH₂F 5-OCH₃ F H A-1217. OCH₂F OCHF₂ 3-F FH A-1218. OCH₂F OCHF₂ 3-CH₃ F H A-1219. OCH₂F OCHF₂ 3-OCH₃ F H A-1220.OCH₂F OCHF₂ 5-F F H A-1221. OCH₂F OCHF₂ 5-CH₃ F H A-1222. OCH₂F OCHF₂5-OCH₃ F H A-1223. OCH₂F OCF₃ 3-F F H A-1224. OCH₂F OCF₃ 3-CH₃ F HA-1225. OCH₂F OCF₃ 3-OCH₃ F H A-1226. OCH₂F OCF₃ 5-F F H A-1227. OCH₂FOCF₃ 5-CH₃ F H A-1228. OCH₂F OCF₃ 5-OCH₃ F H A-1229. OCHF₂ F 3-F F HA-1230. OCHF₂ F 3-CH₃ F H A-1231. OCHF₂ F 3-OCH₃ F H A-1232. OCHF₂ F 5-FF H A-1233. OCHF₂ F 5-CH₃ F H A-1234. OCHF₂ F 5-OCH₃ F H A-1235. OCHF₂CH₃ 3-F F H A-1236. OCHF₂ CH₃ 3-CH₃ F H A-1237. OCHF₂ CH₃ 3-OCH₃ F HA-1238. OCHF₂ CH₃ 5-F F H A-1239. OCHF₂ CH₃ 5-CH₃ F H A-1240. OCHF₂ CH₃5-OCH₃ F H A-1241. OCHF₂ OCH₃ 3-F F H A-1242. OCHF₂ OCH₃ 3-CH₃ F HA-1243. OCHF₂ OCH₃ 3-OCH₃ F H A-1244. OCHF₂ OCH₃ 5-F F H A-1245. OCHF₂OCH₃ 5-CH₃ F H A-1246. OCHF₂ OCH₃ 5-OCH₃ F H A-1247. OCHF₂ CN 3-F F HA-1248. OCHF₂ CN 3-CH₃ F H A-1249. OCHF₂ CN 3-OCH₃ F H A-1250. OCHF₂ CN5-F F H A-1251. OCHF₂ CN 5-CH₃ F H A-1252. OCHF₂ CN 5-OCH₃ F H A-1253.OCHF₂ CH₂F 3-F F H A-1254. OCHF₂ CH₂F 3-CH₃ F H A-1255. OCHF₂ CH₂F3-OCH₃ F H A-1256. OCHF₂ CH₂F 5-F F H A-1257. OCHF₂ CH₂F 5-CH₃ F HA-1258. OCHF₂ CH₂F 5-OCH₃ F H A-1259. OCHF₂ CHF₂ 3-F F H A-1260. OCHF₂CHF₂ 3-CH₃ F H A-1261. OCHF₂ CHF₂ 3-OCH₃ F H A-1262. OCHF₂ CHF₂ 5-F F HA-1263. OCHF₂ CHF₂ 5-CH₃ F H A-1264. OCHF₂ CHF₂ 5-OCH₃ F H A-1265. OCHF₂CF₃ 3-F F H A-1266. OCHF₂ CF₃ 3-CH₃ F H A-1267. OCHF₂ CF₃ 3-OCH₃ F HA-1268. OCHF₂ CF₃ 5-F F H A-1269. OCHF₂ CF₃ 5-CH₃ F H A-1270. OCHF₂ CF₃5-OCH₃ F H A-1271. OCHF₂ OCH₂F 3-F F H A-1272. OCHF₂ OCH₂F 3-CH₃ F HA-1273. OCHF₂ OCH₂F 3-OCH₃ F H A-1274. OCHF₂ OCH₂F 5-F F H A-1275. OCHF₂OCH₂F 5-CH₃ F H A-1276. OCHF₂ OCH₂F 5-OCH₃ F H A-1277. OCHF₂ OCHF₂ 3-F FH A-1278. OCHF₂ OCHF₂ 3-CH₃ F H A-1279. OCHF₂ OCHF₂ 3-OCH₃ F H A-1280.OCHF₂ OCHF₂ 5-F F H A-1281. OCHF₂ OCHF₂ 5-CH₃ F H A-1282. OCHF₂ OCHF₂5-OCH₃ F H A-1283. OCHF₂ OCF₃ 3-F F H A-1284. OCHF₂ OCF₃ 3-CH₃ F HA-1285. OCHF₂ OCF₃ 3-OCH₃ F H A-1286. OCHF₂ OCF₃ 5-F F H A-1287. OCHF₂OCF₃ 5-CH₃ F H A-1288. OCHF₂ OCF₃ 5-OCH₃ F H A-1289. OCF₃ F 3-F F HA-1290. OCF₃ F 3-CH₃ F H A-1291. OCF₃ F 3-OCH₃ F H A-1292. OCF₃ F 5-F FH A-1293. OCF₃ F 5-CH₃ F H A-1294. OCF₃ F 5-OCH₃ F H A-1295. OCF₃ CH₃3-F F H A-1296. OCF₃ CH₃ 3-CH₃ F H A-1297. OCF₃ CH₃ 3-OCH₃ F H A-1298.OCF₃ CH₃ 5-F F H A-1299. OCF₃ CH₃ 5-CH₃ F H A-1300. OCF₃ CH₃ 5-OCH₃ F HA-1301. OCF₃ OCH₃ 3-F F H A-1302. OCF₃ OCH₃ 3-CH₃ F H A-1303. OCF₃ OCH₃3-OCH₃ F H A-1304. OCF₃ OCH₃ 5-F F H A-1305. OCF₃ OCH₃ 5-CH₃ F H A-1306.OCF₃ OCH₃ 5-OCH₃ F H A-1307. OCF₃ CN 3-F F H A-1308. OCF₃ CN 3-CH₃ F HA-1309. OCF₃ CN 3-OCH₃ F H A-1310. OCF₃ CN 5-F F H A-1311. OCF₃ CN 5-CH₃F H A-1312. OCF₃ CN 5-OCH₃ F H A-1313. OCF₃ CH₂F 3-F F H A-1314. OCF₃CH₂F 3-CH₃ F H A-1315. OCF₃ CH₂F 3-OCH₃ F H A-1316. OCF₃ CH₂F 5-F F HA-1317. OCF₃ CH₂F 5-CH₃ F H A-1318. OCF₃ CH₂F 5-OCH₃ F H A-1319. OCF₃CHF₂ 3-F F H A-1320. OCF₃ CHF₂ 3-CH₃ F H A-1321. OCF₃ CHF₂ 3-OCH₃ F HA-1322. OCF₃ CHF₂ 5-F F H A-1323. OCF₃ CHF₂ 5-CH₃ F H A-1324. OCF₃ CHF₂5-OCH₃ F H A-1325. OCF₃ CF₃ 3-F F H A-1326. OCF₃ CF₃ 3-CH₃ F H A-1327.OCF₃ CF₃ 3-OCH₃ F H A-1328. OCF₃ CF₃ 5-F F H A-1329. OCF₃ CF₃ 5-CH₃ F HA-1330. OCF₃ CF₃ 5-OCH₃ F H A-1331. OCF₃ OCH₂F 3-F F H A-1332. OCF₃OCH₂F 3-CH₃ F H A-1333. OCF₃ OCH₂F 3-OCH₃ F H A-1334. OCF₃ OCH₂F 5-F F HA-1335. OCF₃ OCH₂F 5-CH₃ F H A-1336. OCF₃ OCH₂F 5-OCH₃ F H A-1337. OCF₃OCHF₂ 3-F F H A-1338. OCF₃ OCHF₂ 3-CH₃ F H A-1339. OCF₃ OCHF₂ 3-OCH₃ F HA-1340. OCF₃ OCHF₂ 5-F F H A-1341. OCF₃ OCHF₂ 5-CH₃ F H A-1342. OCF₃OCHF₂ 5-OCH₃ F H A-1343. OCF₃ OCF₃ 3-F F H A-1344. OCF₃ OCF₃ 3-CH₃ F HA-1345. OCF₃ OCF₃ 3-OCH₃ F H A-1346. OCF₃ OCF₃ 5-F F H A-1347. OCF₃ OCF₃5-CH₃ F H A-1348. OCF₃ OCF₃ 5-OCH₃ F H A-1349. H H H Cl H A-1350. F H HCl H A-1351. CH₃ H H Cl H A-1352. OCH₃ H H Cl H A-1353. CH₂F H H Cl HA-1354. CHF₂ H H Cl H A-1355. CF₃ H H Cl H A-1356. OCH₂F H H Cl HA-1357. OCHF₂ H H Cl H A-1358. OCF₃ H H Cl H A-1359. H F H Cl H A-1360.H CH₃ H Cl H A-1361. H OCH₃ H Cl H A-1362. H CN H Cl H A-1363. H CH₂F HCl H A-1364. H CHF₂ H Cl H A-1365. H CF₃ H Cl H A-1366. H OCH₂F H Cl HA-1367. H OCHF₂ H Cl H A-1368. H OCF₃ H Cl H A-1369. H H 3-F Cl HA-1370. H H 3-CH₃ Cl H A-1371. H H 3-OCH₃ Cl H A-1372. H H 5-F Cl HA-1373. H H 5-CH₃ Cl H A-1374. H H 5-OCH₃ Cl H A-1375. F F H Cl HA-1376. F CH₃ H Cl H A-1377. F OCH₃ H Cl H A-1378. F CN H Cl H A-1379. FCH₂F H Cl H A-1380. F CHF₂ H Cl H A-1381. F CF₃ H Cl H A-1382. F OCH₂F HCl H A-1383. F OCHF₂ H Cl H A-1384. F OCF₃ H Cl H A-1385. F H 3-F Cl HA-1386. F H 3-CH₃ Cl H A-1387. F H 3-OCH₃ Cl H A-1388. F H 5-F Cl HA-1389. F H 5-CH₃ Cl H A-1390. F H 5-OCH₃ Cl H A-1391. CH₃ F H Cl HA-1392. CH₃ CH₃ H Cl H A-1393. CH₃ OCH₃ H Cl H A-1394. CH₃ CN H Cl HA-1395. CH₃ CH₂F H Cl H A-1396. CH₃ CHF₂ H Cl H A-1397. CH₃ CF₃ H Cl HA-1398. CH₃ OCH₂F H Cl H A-1399. CH₃ OCHF₂ H Cl H A-1400. CH₃ OCF₃ H ClH A-1401. CH₃ H 3-F Cl H A-1402. CH₃ H 3-CH₃ Cl H A-1403. CH₃ H 3-OCH₃Cl H A-1404. CH₃ H 5-F Cl H A-1405. CH₃ H 5-CH₃ Cl H A-1406. CH₃ H5-OCH₃ Cl H A-1407. OCH₃ F H Cl H A-1408. OCH₃ CH₃ H Cl H A-1409. OCH₃OCH₃ H Cl H A-1410. OCH₃ CN H Cl H A-1411. OCH₃ CH₂F H Cl H A-1412. OCH₃CHF₂ H Cl H A-1413. OCH₃ CF₃ H Cl H A-1414. OCH₃ OCH₂F H Cl H A-1415.OCH₃ OCHF₂ H Cl H A-1416. OCH₃ OCF₃ H Cl H A-1417. OCH₃ H 3-F Cl HA-1418. OCH₃ H 3-CH₃ Cl H A-1419. OCH₃ H 3-OCH₃ Cl H A-1420. OCH₃ H 5-FCl H A-1421. OCH₃ H 5-CH₃ Cl H A-1422. OCH₃ H 5-OCH₃ Cl H A-1423. H F3-F Cl H A-1424. H F 3-CH₃ Cl H A-1425. H F 3-OCH₃ Cl H A-1426. H F 5-FCl H A-1427. H F 5-CH₃ Cl H A-1428. H F 5-OCH₃ Cl H A-1429. H CH₃ 3-F ClH A-1430. H CH₃ 3-CH₃ Cl H A-1431. H CH₃ 3-OCH₃ Cl H A-1432. H CH₃ 5-FCl H A-1433. H CH₃ 5-CH₃ Cl H A-1434. H CH₃ 5-OCH₃ Cl H A-1435. H OCH₃3-F Cl H A-1436. H OCH₃ 3-CH₃ Cl H A-1437. H OCH₃ 3-OCH₃ Cl H A-1438. HOCH₃ 5-F Cl H A-1439. H OCH₃ 5-CH₃ Cl H A-1440. H OCH₃ 5-OCH₃ Cl HA-1441. H CN 3-F Cl H A-1442. H CN 3-CH₃ Cl H A-1443. H CN 3-OCH₃ Cl HA-1444. H CN 5-F Cl H A-1445. H CN 5-CH₃ Cl H A-1446. H CN 5-OCH₃ Cl HA-1447. H CH₂F 3-F Cl H A-1448. H CH₂F 3-CH₃ Cl H A-1449. H CH₂F 3-OCH₃Cl H A-1450. H CH₂F 5-F Cl H A-1451. H CH₂F 5-CH₃ Cl H A-1452. H CH₂F5-OCH₃ Cl H A-1453. H CHF₂ 3-F Cl H A-1454. H CHF₂ 3-CH₃ Cl H A-1455. HCHF₂ 3-OCH₃ Cl H A-1456. H CHF₂ 5-F Cl H A-1457. H CHF₂ 5-CH₃ Cl HA-1458. H CHF₂ 5-OCH₃ Cl H A-1459. H CF₃ 3-F Cl H A-1460. H CF₃ 3-CH₃ ClH A-1461. H CF₃ 3-OCH₃ Cl H A-1462. H CF₃ 5-F Cl H A-1463. H CF₃ 5-CH₃Cl H A-1464. H CF₃ 5-OCH₃ Cl H A-1465. H OCH₂F 3-F Cl H A-1466. H OCH₂F3-CH₃ Cl H A-1467. H OCH₂F 3-OCH₃ Cl H A-1468. H OCH₂F 5-F Cl H A-1469.H OCH₂F 5-CH₃ Cl H A-1470. H OCH₂F 5-OCH₃ Cl H A-1471. H OCHF₂ 3-F Cl HA-1472. H OCHF₂ 3-CH₃ Cl H A-1473. H OCHF₂ 3-OCH₃ Cl H A-1474. H OCHF₂5-F Cl H A-1475. H OCHF₂ 5-CH₃ Cl H A-1476. H OCHF₂ 5-OCH₃ Cl H A-1477.H OCF₃ 3-F Cl H A-1478. H OCF₃ 3-CH₃ Cl H A-1479. H OCF₃ 3-OCH₃ Cl HA-1480. H OCF₃ 5-F Cl H A-1481. H OCF₃ 5-CH₃ Cl H A-1482. H OCF₃ 5-OCH₃Cl H A-1483. F F 3-F Cl H A-1484. F F 3-CH₃ Cl H A-1485. F F 3-OCH₃ Cl HA-1486. F F 5-F Cl H A-1487. F F 5-CH₃ Cl H A-1488. F F 5-OCH₃ Cl HA-1489. F CH₃ 3-F Cl H A-1490. F CH₃ 3-CH₃ Cl H A-1491. F CH₃ 3-OCH₃ ClH A-1492. F CH₃ 5-F Cl H A-1493. F CH₃ 5-CH₃ Cl H A-1494. F CH₃ 5-OCH₃Cl H A-1495. F OCH₃ 3-F Cl H A-1496. F OCH₃ 3-CH₃ Cl H A-1497. F OCH₃3-OCH₃ Cl H A-1498. F OCH₃ 5-F Cl H A-1499. F OCH₃ 5-CH₃ Cl H A-1500. FOCH₃ 5-OCH₃ Cl H A-1501. F CN 3-F Cl H A-1502. F CN 3-CH₃ Cl H A-1503. FCN 3-OCH₃ Cl H A-1504. F CN 5-F Cl H A-1505. F CN 5-CH₃ Cl H A-1506. FCN 5-OCH₃ Cl H A-1507. F CH₂F 3-F Cl H A-1508. F CH₂F 3-CH₃ Cl H A-1509.F CH₂F 3-OCH₃ Cl H A-1510. F CH₂F 5-F Cl H A-1511. F CH₂F 5-CH₃ Cl HA-1512. F CH₂F 5-OCH₃ Cl H A-1513. F CHF₂ 3-F Cl H A-1514. F CHF₂ 3-CH₃Cl H A-1515. F CHF₂ 3-OCH₃ Cl H A-1516. F CHF₂ 5-F Cl H A-1517. F CHF₂5-CH₃ Cl H A-1518. F CHF₂ 5-OCH₃ Cl H A-2807. H CF₃ 3-F F F A-2808. HCF₃ 3-CH₃ F F A-2809. H CF₃ 3-OCH₃ F F A-2810. H CF₃ 5-F F F A-2811. HCF₃ 5-CH₃ F F A-2812. H CF₃ 5-OCH₃ F F A-2813. H OCH₂F 3-F F F A-2814. HOCH₂F 3-CH₃ F F A-2815. H OCH₂F 3-OCH₃ F F A-2816. H OCH₂F 5-F F FA-2817. H OCH₂F 5-CH₃ F F A-2818. H OCH₂F 5-OCH₃ F F A-2819. H OCHF₂ 3-FF F A-2820. H OCHF₂ 3-CH₃ F F A-2821. H OCHF₂ 3-OCH₃ F F A-2822. H OCHF₂5-F F F A-2823. H OCHF₂ 5-CH₃ F F A-2824. H OCHF₂ 5-OCH₃ F F A-2825. HOCF₃ 3-F F F A-2826. H OCF₃ 3-CH₃ F F A-2827. H OCF₃ 3-OCH₃ F F A-2828.H OCF₃ 5-F F F A-2829. H OCF₃ 5-CH₃ F F A-2830. H OCF₃ 5-OCH₃ F FA-2831. F F 3-F F F A-2832. F F 3-CH₃ F F A-2833. F F 3-OCH₃ F F A-2834.F F 5-F F F A-2835. F F 5-CH₃ F F A-2836. F F 5-OCH₃ F F A-2837. F CH₃3-F F F A-2838. F CH₃ 3-CH₃ F F A-2839. F CH₃ 3-OCH₃ F F A-2840. F CH₃5-F F F A-2841. F CH₃ 5-CH₃ F F A-2842. F CH₃ 5-OCH₃ F F A-2843. F OCH₃3-F F F A-2844. F OCH₃ 3-CH₃ F F A-2845. F OCH₃ 3-OCH₃ F F A-2846. FOCH₃ 5-F F F A-2847. F OCH₃ 5-CH₃ F F A-2848. F OCH₃ 5-OCH₃ F F A-2849.F CN 3-F F F A-2850. F CN 3-CH₃ F F A-2851. F CN 3-OCH₃ F F A-2852. F CN5-F F F A-2853. F CN 5-CH₃ F F A-2854. F CN 5-OCH₃ F F A-2855. F CH₂F3-F F F A-2856. F CH₂F 3-CH₃ F F A-2857. F CH₂F 3-OCH₃ F F A-2858. FCH₂F 5-F F F A-2859. F CH₂F 5-CH₃ F F A-2860. F CH₂F 5-OCH₃ F F A-2861.F CHF₂ 3-F F F A-2862. F CHF₂ 3-CH₃ F F A-2863. F CHF₂ 3-OCH₃ F FA-2864. F CHF₂ 5-F F F A-2865. F CHF₂ 5-CH₃ F F A-2866. F CHF₂ 5-OCH₃ FF A-2867. F CF₃ 3-F F F A-2868. F CF₃ 3-CH₃ F F A-2869. F CF₃ 3-OCH₃ F FA-2870. F CF₃ 5-F F F A-2871. F CF₃ 5-CH₃ F F A-2872. F CF₃ 5-OCH₃ F FA-2873. F OCH₂F 3-F F F A-2874. F OCH₂F 3-CH₃ F F A-2875. F OCH₂F 3-OCH₃F F A-2876. F OCH₂F 5-F F F A-2877. F OCH₂F 5-CH₃ F F A-2878. F OCH₂F5-OCH₃ F F A-2879. F OCHF₂ 3-F F F A-2880. F OCHF₂ 3-CH₃ F F A-2881. FOCHF₂ 3-OCH₃ F F A-2882. F OCHF₂ 5-F F F A-2883. F OCHF₂ 5-CH₃ F FA-2884. F OCHF₂ 5-OCH₃ F F A-2885. F OCF₃ 3-F F F A-2886. F OCF₃ 3-CH₃ FF A-2887. F OCF₃ 3-OCH₃ F F A-2888. F OCF₃ 5-F F F A-2889. F OCF₃ 5-CH₃F F A-2890. F OCF₃ 5-OCH₃ F F A-2891. CH₃ F 3-F F F A-2892. CH₃ F 3-CH₃F F A-2893. CH₃ F 3-OCH₃ F F A-2894. CH₃ F 5-F F F A-2895. CH₃ F 5-CH₃ FF A-2896. CH₃ F 5-OCH₃ F F A-2897. CH₃ CH₃ 3-F F F A-2898. CH₃ CH₃ 3-CH₃F F A-2899. CH₃ CH₃ 3-OCH₃ F F A-2900. CH₃ CH₃ 5-F F F A-2901. CH₃ CH₃5-CH₃ F F A-2902. CH₃ CH₃ 5-OCH₃ F F A-2903. CH₃ OCH₃ 3-F F F A-2904.CH₃ OCH₃ 3-CH₃ F F A-2905. CH₃ OCH₃ 3-OCH₃ F F A-2906. CH₃ OCH₃ 5-F F FA-2907. CH₃ OCH₃ 5-CH₃ F F A-2908. CH₃ OCH₃ 5-OCH₃ F F A-2909. CH₃ CN3-F F F A-2910. CH₃ CN 3-CH₃ F F A-2911. CH₃ CN 3-OCH₃ F F A-2912. CH₃CN 5-F F F A-2913. CH₃ CN 5-CH₃ F F A-2914. CH₃ CN 5-OCH₃ F F A-2915.CH₃ CH₂F 3-F F F A-2916. CH₃ CH₂F 3-CH₃ F F A-2917. CH₃ CH₂F 3-OCH₃ F FA-2918. CH₃ CH₂F 5-F F F A-2919. CH₃ CH₂F 5-CH₃ F F A-2920. CH₃ CH₂F5-OCH₃ F F A-2921. CH₃ CHF₂ 3-F F F A-2922. CH₃ CHF₂ 3-CH₃ F F A-2923.CH₃ CHF₂ 3-OCH₃ F F A-2924. CH₃ CHF₂ 5-F F F A-2925. CH₃ CHF₂ 5-CH₃ F FA-2926. CH₃ CHF₂ 5-OCH₃ F F A-2927. CH₃ CF₃ 3-F F F A-2928. CH₃ CF₃3-CH₃ F F A-2929. CH₃ CF₃ 3-OCH₃ F F A-2930. CH₃ CF₃ 5-F F F A-2931. CH₃CF₃ 5-CH₃ F F A-2932. CH₃ CF₃ 5-OCH₃ F F A-2933. CH₃ OCH₂F 3-F F FA-2934. CH₃ OCH₂F 3-CH₃ F F A-2935. CH₃ OCH₂F 3-OCH₃ F F A-2936. CH₃OCH₂F 5-F F F A-2937. CH₃ OCH₂F 5-CH₃ F F A-2938. CH₃ OCH₂F 5-OCH₃ F FA-2939. CH₃ OCHF₂ 3-F F F A-2940. CH₃ OCHF₂ 3-CH₃ F F A-2941. CH₃ OCHF₂3-OCH₃ F F A-2942. CH₃ OCHF₂ 5-F F F A-2943. CH₃ OCHF₂ 5-CH₃ F F A-2944.CH₃ OCHF₂ 5-OCH₃ F F A-2945. CH₃ OCF₃ 3-F F F A-2946. CH₃ OCF₃ 3-CH₃ F FA-2947. CH₃ OCF₃ 3-OCH₃ F F A-2948. CH₃ OCF₃ 5-F F F A-2949. CH₃ OCF₃5-CH₃ F F A-2950. CH₃ OCF₃ 5-OCH₃ F F A-2951. OCH₃ F 3-F F F A-2952.OCH₃ F 3-CH₃ F F A-2953. OCH₃ F 3-OCH₃ F F A-2954. OCH₃ F 5-F F FA-2955. OCH₃ F 5-CH₃ F F A-2956. OCH₃ F 5-OCH₃ F F A-2957. OCH₃ CH₃ 3-FF F A-2958. OCH₃ CH₃ 3-CH₃ F F A-2959. OCH₃ CH₃ 3-OCH₃ F F A-2960. OCH₃CH₃ 5-F F F A-2961. OCH₃ CH₃ 5-CH₃ F F A-2962. OCH₃ CH₃ 5-OCH₃ F FA-2963. OCH₃ OCH₃ 3-F F F A-2964. OCH₃ OCH₃ 3-CH₃ F F A-2965. OCH₃ OCH₃3-OCH₃ F F A-2966. OCH₃ OCH₃ 5-F F F A-2967. OCH₃ OCH₃ 5-CH₃ F F A-2968.OCH₃ OCH₃ 5-OCH₃ F F A-2969. OCH₃ CN 3-F F F A-2970. OCH₃ CN 3-CH₃ F FA-2971. OCH₃ CN 3-OCH₃ F F A-2972. OCH₃ CN 5-F F F A-2973. OCH₃ CN 5-CH₃F F A-2974. OCH₃ CN 5-OCH₃ F F A-2975. OCH₃ CH₂F 3-F F F A-2976. OCH₃CH₂F 3-CH₃ F F A-2977. OCH₃ CH₂F 3-OCH₃ F F A-2978. OCH₃ CH₂F 5-F F FA-2979. OCH₃ CH₂F 5-CH₃ F F A-2980. OCH₃ CH₂F 5-OCH₃ F F A-2981. OCH₃CHF₂ 3-F F F A-2982. OCH₃ CHF₂ 3-CH₃ F F A-2983. OCH₃ CHF₂ 3-OCH₃ F FA-2984. OCH₃ CHF₂ 5-F F F A-2985. OCH₃ CHF₂ 5-CH₃ F F A-2986. OCH₃ CHF₂5-OCH₃ F F A-2987. OCH₃ CF₃ 3-F F F A-2988. OCH₃ CF₃ 3-CH₃ F F A-2989.OCH₃ CF₃ 3-OCH₃ F F A-2990. OCH₃ CF₃ 5-F F F A-2991. OCH₃ CF₃ 5-CH₃ F FA-2992. OCH₃ CF₃ 5-OCH₃ F F A-2993. OCH₃ OCH₂F 3-F F F A-2994. OCH₃OCH₂F 3-CH₃ F F A-2995. OCH₃ OCH₂F 3-OCH₃ F F A-2996. OCH₃ OCH₂F 5-F F FA-2997. OCH₃ OCH₂F 5-CH₃ F F A-2998. OCH₃ OCH₂F 5-OCH₃ F F A-2999. OCH₃OCHF₂ 3-F F F A-3000. OCH₃ OCHF₂ 3-CH₃ F F A-3001. OCH₃ OCHF₂ 3-OCH₃ F FA-3002. OCH₃ OCHF₂ 5-F F F A-3003. OCH₃ OCHF₂ 5-CH₃ F F A-3004. OCH₃OCHF₂ 5-OCH₃ F F A-3005. OCH₃ OCF₃ 3-F F F A-3006. OCH₃ OCF₃ 3-CH₃ F FA-3007. OCH₃ OCF₃ 3-OCH₃ F F A-3008. OCH₃ OCF₃ 5-F F F A-3009. OCH₃ OCF₃5-CH₃ F F A-3010. OCH₃ OCF₃ 5-OCH₃ F F A-3011. CH₂F F 3-F F F A-3012.CH₂F F 3-CH₃ F F A-3013. CH₂F F 3-OCH₃ F F A-3014. CH₂F F 5-F F FA-3015. CH₂F F 5-CH₃ F F A-3016. CH₂F F 5-OCH₃ F F A-3017. CH₂F CH₃ 3-FF F A-3018. CH₂F CH₃ 3-CH₃ F F A-3019. CH₂F CH₃ 3-OCH₃ F F A-3020. CH₂FCH₃ 5-F F F A-3021. CH₂F CH₃ 5-CH₃ F F A-3022. CH₂F CH₃ 5-OCH₃ F FA-3023. CH₂F OCH₃ 3-F F F A-3024. CH₂F OCH₃ 3-CH₃ F F A-3025. CH₂F OCH₃3-OCH₃ F F A-3026. CH₂F OCH₃ 5-F F F A-3027. CH₂F OCH₃ 5-CH₃ F F A-3028.CH₂F OCH₃ 5-OCH₃ F F A-3029. CH₂F CN 3-F F F A-3030. CH₂F CN 3-CH₃ F FA-3031. CH₂F CN 3-OCH₃ F F A-3032. CH₂F CN 5-F F F A-3033. CH₂F CN 5-CH₃F F A-3034. CH₂F CN 5-OCH₃ F F A-3035. CH₂F CH₂F 3-F F F A-3036. CH₂FCH₂F 3-CH₃ F F A-3037. CH₂F CH₂F 3-OCH₃ F F A-3038. CH₂F CH₂F 5-F F FA-3039. CH₂F CH₂F 5-CH₃ F F A-3040. CH₂F CH₂F 5-OCH₃ F F A-3041. CH₂FCHF₂ 3-F F F A-3042. CH₂F CHF₂ 3-CH₃ F F A-3043. CH₂F CHF₂ 3-OCH₃ F FA-3044. CH₂F CHF₂ 5-F F F A-3045. CH₂F CHF₂ 5-CH₃ F F A-3046. CH₂F CHF₂5-OCH₃ F F A-3047. CH₂F CF₃ 3-F F F A-3048. CH₂F CF₃ 3-CH₃ F F A-3049.CH₂F CF₃ 3-OCH₃ F F A-3050. CH₂F CF₃ 5-F F F A-3051. CH₂F CF₃ 5-CH₃ F FA-3052. CH₂F CF₃ 5-OCH₃ F F A-3053. CH₂F OCH₂F 3-F F F A-3054. CH₂FOCH₂F 3-CH₃ F F A-3055. CH₂F OCH₂F 3-OCH₃ F F A-3056. CH₂F OCH₂F 5-F F FA-3057. CH₂F OCH₂F 5-CH₃ F F A-3058. CH₂F OCH₂F 5-OCH₃ F F A-3059. CH₂FOCHF₂ 3-F F F A-3060. CH₂F OCHF₂ 3-CH₃ F F A-3061. CH₂F OCHF₂ 3-OCH₃ F FA-3062. CH₂F OCHF₂ 5-F F F A-3063. CH₂F OCHF₂ 5-CH₃ F F A-3064. CH₂FOCHF₂ 5-OCH₃ F F A-3065. CH₂F OCF₃ 3-F F F A-3066. CH₂F OCF₃ 3-CH₃ F FA-3067. CH₂F OCF₃ 3-OCH₃ F F A-3068. CH₂F OCF₃ 5-F F F A-3069. CH₂F OCF₃5-CH₃ F F A-3070. CH₂F OCF₃ 5-OCH₃ F F A-3071. CHF₂ F 3-F F F A-3072.CHF₂ F 3-CH₃ F F A-3073. CHF₂ F 3-OCH₃ F F A-3074. CHF₂ F 5-F F FA-3075. CHF₂ F 5-CH₃ F F A-3076. CHF₂ F 5-OCH₃ F F A-3077. CHF₂ CH₃ 3-FF F A-3078. CHF₂ CH₃ 3-CH₃ F F A-3079. CHF₂ CH₃ 3-OCH₃ F F A-3080. CHF₂CH₃ 5-F F F A-3081. CHF₂ CH₃ 5-CH₃ F F A-3082. CHF₂ CH₃ 5-OCH₃ F FA-3083. CHF₂ OCH₃ 3-F F F A-3084. CHF₂ OCH₃ 3-CH₃ F F A-3085. CHF₂ OCH₃3-OCH₃ F F A-3086. CHF₂ OCH₃ 5-F F F A-3087. CHF₂ OCH₃ 5-CH₃ F F A-3088.CHF₂ OCH₃ 5-OCH₃ F F A-3089. CHF₂ CN 3-F F F A-3090. CHF₂ CN 3-CH₃ F FA-3091. CHF₂ CN 3-OCH₃ F F A-3092. CHF₂ CN 5-F F F A-3093. CHF₂ CN 5-CH₃F F A-3094. CHF₂ CN 5-OCH₃ F F A-3095. CHF₂ CH₂F 3-F F F A-3096. CHF₂CH₂F 3-CH₃ F F A-3097. CHF₂ CH₂F 3-OCH₃ F F A-3098. CHF₂ CH₂F 5-F F FA-3099. CHF₂ CH₂F 5-CH₃ F F A-3100. CHF₂ CH₂F 5-OCH₃ F F A-3101. CHF₂CHF₂ 3-F F F A-3102. CHF₂ CHF₂ 3-CH₃ F F A-3103. CHF₂ CHF₂ 3-OCH₃ F FA-3104. CHF₂ CHF₂ 5-F F F A-3105. CHF₂ CHF₂ 5-CH₃ F F A-3106. CHF₂ CHF₂5-OCH₃ F F A-3107. CHF₂ CF₃ 3-F F F A-3108. CHF₂ CF₃ 3-CH₃ F F A-3109.CHF₂ CF₃ 3-OCH₃ F F A-3110. CHF₂ CF₃ 5-F F F A-3111. CHF₂ CF₃ 5-CH₃ F FA-3112. CHF₂ CF₃ 5-OCH₃ F F A-3113. CHF₂ OCH₂F 3-F F F A-3114. CHF₂OCH₂F 3-CH₃ F F A-3115. CHF₂ OCH₂F 3-OCH₃ F F A-3116. CHF₂ OCH₂F 5-F F FA-3117. CHF₂ OCH₂F 5-CH₃ F F A-3118. CHF₂ OCH₂F 5-OCH₃ F F A-3119. CHF₂OCHF₂ 3-F F F A-3120. CHF₂ OCHF₂ 3-CH₃ F F A-3121. CHF₂ OCHF₂ 3-OCH₃ F FA-3122. CHF₂ OCHF₂ 5-F F F A-3123. CHF₂ OCHF₂ 5-CH₃ F F A-3124. CHF₂OCHF₂ 5-OCH₃ F F A-3125. CHF₂ OCF₃ 3-F F F A-3126. CHF₂ OCF₃ 3-CH₃ F FA-3127. CHF₂ OCF₃ 3-OCH₃ F F A-3128. CHF₂ OCF₃ 5-F F F A-3129. CHF₂ OCF₃5-CH₃ F F A-3130. CHF₂ OCF₃ 5-OCH₃ F F A-3131. CF₃ F 3-F F F A-3132. CF₃F 3-CH₃ F F A-3133. CF₃ F 3-OCH₃ F F A-3134. CF₃ F 5-F F F A-3135. CF₃ F5-CH₃ F F A-3136. CF₃ F 5-OCH₃ F F A-3137. CF₃ CH₃ 3-F F F A-3138. CF₃CH₃ 3-CH₃ F F A-3139. CF₃ CH₃ 3-OCH₃ F F A-3140. CF₃ CH₃ 5-F F F A-3141.CF₃ CH₃ 5-CH₃ F F A-3142. CF₃ CH₃ 5-OCH₃ F F A-3143. CF₃ OCH₃ 3-F F FA-3144. CF₃ OCH₃ 3-CH₃ F F A-3145. CF₃ OCH₃ 3-OCH₃ F F A-3146. CF₃ OCH₃5-F F F A-3147. CF₃ OCH₃ 5-CH₃ F F A-3148. CF₃ OCH₃ 5-OCH₃ F F A-3149.CF₃ CN 3-F F F A-3150. CF₃ CN 3-CH₃ F F A-3151. CF₃ CN 3-OCH₃ F FA-3152. CF₃ CN 5-F F F A-3153. CF₃ CN 5-CH₃ F F A-3154. CF₃ CN 5-OCH₃ FF A-3155. CF₃ CH₂F 3-F F F A-3156. CF₃ CH₂F 3-CH₃ F F A-3157. CF₃ CH₂F3-OCH₃ F F A-3158. CF₃ CH₂F 5-F F F A-3159. CF₃ CH₂F 5-CH₃ F F A-3160.CF₃ CH₂F 5-OCH₃ F F A-3161. CF₃ CHF₂ 3-F F F A-3162. CF₃ CHF₂ 3-CH₃ F FA-3163. CF₃ CHF₂ 3-OCH₃ F F A-3164. CF₃ CHF₂ 5-F F F A-3165. CF₃ CHF₂5-CH₃ F F A-3166. CF₃ CHF₂ 5-OCH₃ F F A-3167. CF₃ CF₃ 3-F F F A-3168.CF₃ CF₃ 3-CH₃ F F A-3169. CF₃ CF₃ 3-OCH₃ F F A-3170. CF₃ CF₃ 5-F F FA-3171. CF₃ CF₃ 5-CH₃ F F A-3172. CF₃ CF₃ 5-OCH₃ F F A-3173. CF₃ OCH₂F3-F F F A-3174. CF₃ OCH₂F 3-CH₃ F F A-3175. CF₃ OCH₂F 3-OCH₃ F F A-3176.CF₃ OCH₂F 5-F F F A-3177. CF₃ OCH₂F 5-CH₃ F F A-3178. CF₃ OCH₂F 5-OCH₃ FF A-3179. CF₃ OCHF₂ 3-F F F A-3180. CF₃ OCHF₂ 3-CH₃ F F A-3181. CF₃OCHF₂ 3-OCH₃ F F A-3182. CF₃ OCHF₂ 5-F F F A-3183. CF₃ OCHF₂ 5-CH₃ F FA-3184. CF₃ OCHF₂ 5-OCH₃ F F A-3185. CF₃ OCF₃ 3-F F F A-3186. CF₃ OCF₃3-CH₃ F F A-3187. CF₃ OCF₃ 3-OCH₃ F F A-3188. CF₃ OCF₃ 5-F F F A-3189.CF₃ OCF₃ 5-CH₃ F F A-3190. CF₃ OCF₃ 5-OCH₃ F F A-3191. OCH₂F F 3-F F FA-3192. OCH₂F F 3-CH₃ F F A-3193. OCH₂F F 3-OCH₃ F F A-3194. OCH₂F F 5-FF F A-3195. OCH₂F F 5-CH₃ F F A-3196. OCH₂F F 5-OCH₃ F F A-3197. OCH₂FCH₃ 3-F F F A-3198. OCH₂F CH₃ 3-CH₃ F F A-3199. OCH₂F CH₃ 3-OCH₃ F FA-3200. OCH₂F CH₃ 5-F F F A-3201. OCH₂F CH₃ 5-CH₃ F F A-3202. OCH₂F CH₃5-OCH₃ F F A-3203. OCH₂F OCH₃ 3-F F F A-3204. OCH₂F OCH₃ 3-CH₃ F FA-3205. OCH₂F OCH₃ 3-OCH₃ F F A-3206. OCH₂F OCH₃ 5-F F F A-3207. OCH₂FOCH₃ 5-CH₃ F F A-3208. OCH₂F OCH₃ 5-OCH₃ F F A-3209. OCH₂F CN 3-F F FA-3210. OCH₂F CN 3-CH₃ F F A-3211. OCH₂F CN 3-OCH₃ F F A-3212. OCH₂F CN5-F F F A-3213. OCH₂F CN 5-CH₃ F F A-3214. OCH₂F CN 5-OCH₃ F F A-3215.OCH₂F CH₂F 3-F F F A-3216. OCH₂F CH₂F 3-CH₃ F F A-3217. OCH₂F CH₂F3-OCH₃ F F A-3218. OCH₂F CH₂F 5-F F F A-3219. OCH₂F CH₂F 5-CH₃ F FA-3220. OCH₂F CH₂F 5-OCH₃ F F A-3221. OCH₂F CHF₂ 3-F F F A-3222. OCH₂FCHF₂ 3-CH₃ F F A-3223. OCH₂F CHF₂ 3-OCH₃ F F A-3224. OCH₂F CHF₂ 5-F F FA-3225. OCH₂F CHF₂ 5-CH₃ F F A-3226. OCH₂F CHF₂ 5-OCH₃ F F A-3227. OCH₂FCF₃ 3-F F F A-3228. OCH₂F CF₃ 3-CH₃ F F A-3229. OCH₂F CF₃ 3-OCH₃ F FA-3230. OCH₂F CF₃ 5-F F F A-3231. OCH₂F CF₃ 5-CH₃ F F A-3232. OCH₂F CF₃5-OCH₃ F F A-3233. OCH₂F OCH₂F 3-F F F A-3234. OCH₂F OCH₂F 3-CH₃ F FA-3235. OCH₂F OCH₂F 3-OCH₃ F F A-3236. OCH₂F OCH₂F 5-F F F A-3237. OCH₂FOCH₂F 5-CH₃ F F A-3238. OCH₂F OCH₂F 5-OCH₃ F F A-3239. OCH₂F OCHF₂ 3-F FF A-3240. OCH₂F OCHF₂ 3-CH₃ F F A-3241. OCH₂F OCHF₂ 3-OCH₃ F F A-3242.OCH₂F OCHF₂ 5-F F F A-3243. OCH₂F OCHF₂ 5-CH₃ F F A-3244. OCH₂F OCHF₂5-OCH₃ F F A-3245. OCH₂F OCF₃ 3-F F F A-3246. OCH₂F OCF₃ 3-CH₃ F FA-3247. OCH₂F OCF₃ 3-OCH₃ F F A-3248. OCH₂F OCF₃ 5-F F F A-3249. OCH₂FOCF₃ 5-CH₃ F F A-3250. OCH₂F OCF₃ 5-OCH₃ F F A-3251. OCHF₂ F 3-F F FA-3252. OCHF₂ F 3-CH₃ F F A-3253. OCHF₂ F 3-OCH₃ F F A-3254. OCHF₂ F 5-FF F A-3255. OCHF₂ F 5-CH₃ F F A-3256. OCHF₂ F 5-OCH₃ F F A-3257. OCHF₂CH₃ 3-F F F A-3258. OCHF₂ CH₃ 3-CH₃ F F A-3259. OCHF₂ CH₃ 3-OCH₃ F FA-3260. OCHF₂ CH₃ 5-F F F A-3261. OCHF₂ CH₃ 5-CH₃ F F A-3262. OCHF₂ CH₃5-OCH₃ F F A-3263. OCHF₂ OCH₃ 3-F F F A-3264. OCHF₂ OCH₃ 3-CH₃ F FA-3265. OCHF₂ OCH₃ 3-OCH₃ F F A-3266. OCHF₂ OCH₃ 5-F F F A-3267. OCHF₂OCH₃ 5-CH₃ F F A-3268. OCHF₂ OCH₃ 5-OCH₃ F F A-3269. OCHF₂ CN 3-F F FA-3270. OCHF₂ CN 3-CH₃ F F A-3271. OCHF₂ CN 3-OCH₃ F F A-3272. OCHF₂ CN5-F F F A-3273. OCHF₂ CN 5-CH₃ F F A-3274. OCHF₂ CN 5-OCH₃ F F A-3275.OCHF₂ CH₂F 3-F F F A-3276. OCHF₂ CH₂F 3-CH₃ F F A-3277. OCHF₂ CH₂F3-OCH₃ F F A-3278. OCHF₂ CH₂F 5-F F F A-3279. OCHF₂ CH₂F 5-CH₃ F FA-3280. OCHF₂ CH₂F 5-OCH₃ F F A-3281. OCHF₂ CHF₂ 3-F F F A-3282. OCHF₂CHF₂ 3-CH₃ F F A-3283. OCHF₂ CHF₂ 3-OCH₃ F F A-3284. OCHF₂ CHF₂ 5-F F FA-3285. OCHF₂ CHF₂ 5-CH₃ F F A-3286. OCHF₂ CHF₂ 5-OCH₃ F F A-3287. OCHF₂CF₃ 3-F F F A-3288. OCHF₂ CF₃ 3-CH₃ F F A-3289. OCHF₂ CF₃ 3-OCH₃ F FA-3290. OCHF₂ CF₃ 5-F F F A-3291. OCHF₂ CF₃ 5-CH₃ F F A-3292. OCHF₂ CF₃5-OCH₃ F F A-3293. OCHF₂ OCH₂F 3-F F F A-3294. OCHF₂ OCH₂F 3-CH₃ F FA-3295. OCHF₂ OCH₂F 3-OCH₃ F F A-3296. OCHF₂ OCH₂F 5-F F F A-3297. OCHF₂OCH₂F 5-CH₃ F F A-3298. OCHF₂ OCH₂F 5-OCH₃ F F A-3299. OCHF₂ OCHF₂ 3-F FF A-3300. OCHF₂ OCHF₂ 3-CH₃ F F A-3301. OCHF₂ OCHF₂ 3-OCH₃ F F A-3302.OCHF₂ OCHF₂ 5-F F F A-3303. OCHF₂ OCHF₂ 5-CH₃ F F A-3304. OCHF₂ OCHF₂5-OCH₃ F F A-3305. OCHF₂ OCF₃ 3-F F F A-3306. OCHF₂ OCF₃ 3-CH₃ F FA-3307. OCHF₂ OCF₃ 3-OCH₃ F F A-3308. OCHF₂ OCF₃ 5-F F F A-3309. OCHF₂OCF₃ 5-CH₃ F F A-3310. OCHF₂ OCF₃ 5-OCH₃ F F A-3311. OCF₃ F 3-F F FA-3312. OCF₃ F 3-CH₃ F F A-3313. OCF₃ F 3-OCH₃ F F A-3314. OCF₃ F 5-F FF A-3315. OCF₃ F 5-CH₃ F F A-3316. OCF₃ F 5-OCH₃ F F A-3317. OCF₃ CH₃3-F F F A-3318. OCF₃ CH₃ 3-CH₃ F F A-3319. OCF₃ CH₃ 3-OCH₃ F F A-3320.OCF₃ CH₃ 5-F F F A-3321. OCF₃ CH₃ 5-CH₃ F F A-3322. OCF₃ CH₃ 5-OCH₃ F FA-3323. OCF₃ OCH₃ 3-F F F A-3324. OCF₃ OCH₃ 3-CH₃ F F A-3325. OCF₃ OCH₃3-OCH₃ F F A-3326. OCF₃ OCH₃ 5-F F F A-3327. OCF₃ OCH₃ 5-CH₃ F F A-3328.OCF₃ OCH₃ 5-OCH₃ F F A-3329. OCF₃ CN 3-F F F A-3330. OCF₃ CN 3-CH₃ F FA-3331. OCF₃ CN 3-OCH₃ F F A-3332. OCF₃ CN 5-F F F A-3333. OCF₃ CN 5-CH₃F F A-3334. OCF₃ CN 5-OCH₃ F F A-3335. OCF₃ CH₂F 3-F F F A-3336. OCF₃CH₂F 3-CH₃ F F A-3337. OCF₃ CH₂F 3-OCH₃ F F A-3338. OCF₃ CH₂F 5-F F FA-3339. OCF₃ CH₂F 5-CH₃ F F A-3340. OCF₃ CH₂F 5-OCH₃ F F A-3341. OCF₃CHF₂ 3-F F F A-3342. OCF₃ CHF₂ 3-CH₃ F F A-3343. OCF₃ CHF₂ 3-OCH₃ F FA-3344. OCF₃ CHF₂ 5-F F F A-3345. OCF₃ CHF₂ 5-CH₃ F F A-3346. OCF₃ CHF₂5-OCH₃ F F A-3347. OCF₃ CF₃ 3-F F F A-3348. OCF₃ CF₃ 3-CH₃ F F A-3349.OCF₃ CF₃ 3-OCH₃ F F A-3350. OCF₃ CF₃ 5-F F F A-3351. OCF₃ CF₃ 5-CH₃ F FA-3352. OCF₃ CF₃ 5-OCH₃ F F A-3353. OCF₃ OCH₂F 3-F F F A-3354. OCF₃OCH₂F 3-CH₃ F F A-3355. OCF₃ OCH₂F 3-OCH₃ F F A-3356. OCF₃ OCH₂F 5-F F FA-3357. OCF₃ OCH₂F 5-CH₃ F F A-3358. OCF₃ OCH₂F 5-OCH₃ F F A-3359. OCF₃OCHF₂ 3-F F F A-3360. OCF₃ OCHF₂ 3-CH₃ F F A-3361. OCF₃ OCHF₂ 3-OCH₃ F FA-3362. OCF₃ OCHF₂ 5-F F F A-3363. OCF₃ OCHF₂ 5-CH₃ F F A-3364. OCF₃OCHF₂ 5-OCH₃ F F A-3365. OCF₃ OCF₃ 3-F F F A-3366. OCF₃ OCF₃ 3-CH₃ F FA-3367. OCF₃ OCF₃ 3-OCH₃ F F A-3368. OCF₃ OCF₃ 5-F F F A-3369. OCF₃ OCF₃5-CH₃ F F A-3370. OCF₃ OCF₃ 5-OCH₃ F F A-3371. H H H Cl F A-3372. F H HCl F A-3373. CH₃ H H Cl F A-3374. OCH₃ H H Cl F A-3375. CH₂F H H Cl FA-3376. CHF₂ H H Cl F A-3377. CF₃ H H Cl F A-3378. OCH₂F H H Cl FA-3379. OCHF₂ H H Cl F A-3380. OCF₃ H H Cl F A-3381. H F H Cl F A-3382.H CH₃ H Cl F A-3383. H OCH₃ H Cl F A-3384. H CN H Cl F A-3385. H CH₂F HCl F A-3386. H CHF₂ H Cl F A-3387. H CF₃ H Cl F A-3388. H OCH₂F H Cl FA-3389. H OCHF₂ H Cl F A-3390. H OCF₃ H Cl F A-3391. H H 3-F Cl FA-3392. H H 3-CH₃ Cl F A-3393. H H 3-OCH₃ Cl F A-3394. H H 5-F Cl FA-3395. H H 5-CH₃ Cl F A-3396. H H 5-OCH₃ Cl F A-3397. F F H Cl FA-3398. F CH₃ H Cl F A-3399. F OCH₃ H Cl F A-3400. F CN H Cl F A-3401. FCH₂F H Cl F A-3402. F CHF₂ H Cl F A-3403. F CF₃ H Cl F A-3404. F OCH₂F HCl F A-3405. F OCHF₂ H Cl F A-3406. F OCF₃ H Cl F A-3407. F H 3-F Cl FA-3408. F H 3-CH₃ Cl F A-3409. F H 3-OCH₃ Cl F A-3410. F H 5-F Cl FA-3411. F H 5-CH₃ Cl F A-3412. F H 5-OCH₃ Cl F A-3413. CH₃ F H Cl FA-3414. CH₃ CH₃ H Cl F A-3415. CH₃ OCH₃ H Cl F A-3416. CH₃ CN H Cl FA-3417. CH₃ CH₂F H Cl F A-3418. CH₃ CHF₂ H Cl F A-3419. CH₃ CF₃ H Cl FA-3420. CH₃ OCH₂F H Cl F A-3421. CH₃ OCHF₂ H Cl F A-3422. CH₃ OCF₃ H ClF A-3423. CH₃ H 3-F Cl F A-3424. CH₃ H 3-CH₃ Cl F A-3425. CH₃ H 3-OCH₃Cl F A-3426. CH₃ H 5-F Cl F A-3427. CH₃ H 5-CH₃ Cl F A-3428. CH₃ H5-OCH₃ Cl F A-3429. OCH₃ F H Cl F A-3430. OCH₃ CH₃ H Cl F A-3431. OCH₃OCH₃ H Cl F A-3432. OCH₃ CN H Cl F A-3433. OCH₃ CH₂F H Cl F A-3434. OCH₃CHF₂ H Cl F A-3435. OCH₃ CF₃ H Cl F A-3436. OCH₃ OCH₂F H Cl F A-3437.OCH₃ OCHF₂ H Cl F A-3438. OCH₃ OCF₃ H Cl F A-3439. OCH₃ H 3-F Cl FA-3440. OCH₃ H 3-CH₃ Cl F A-3441. OCH₃ H 3-OCH₃ Cl F A-3442. OCH₃ H 5-FCl F A-3443. OCH₃ H 5-CH₃ Cl F A-3444. OCH₃ H 5-OCH₃ Cl F A-3445. H F3-F Cl F A-3446. H F 3-CH₃ Cl F A-3447. H F 3-OCH₃ Cl F A-3448. H F 5-FCl F A-3449. H F 5-CH₃ Cl F A-3450. H F 5-OCH₃ Cl F A-3451. H CH₃ 3-F ClF A-3452. H CH₃ 3-CH₃ Cl F A-3453. H CH₃ 3-OCH₃ Cl F A-3454. H CH₃ 5-FCl F A-3455. H CH₃ 5-CH₃ Cl F A-3456. H CH₃ 5-OCH₃ Cl F A-3457. H OCH₃3-F Cl F A-3458. H OCH₃ 3-CH₃ Cl F A-3459. H OCH₃ 3-OCH₃ Cl F A-3460. HOCH₃ 5-F Cl F A-3461. H OCH₃ 5-CH₃ Cl F A-3462. H OCH₃ 5-OCH₃ Cl FA-3463. H CN 3-F Cl F A-3464. H CN 3-CH₃ Cl F A-3465. H CN 3-OCH₃ Cl FA-3466. H CN 5-F Cl F A-3467. H CN 5-CH₃ Cl F A-3468. H CN 5-OCH₃ Cl FA-3469. H CH₂F 3-F Cl F A-3470. H CH₂F 3-CH₃ Cl F A-3471. H CH₂F 3-OCH₃Cl F A-3472. H CH₂F 5-F Cl F A-3473. H CH₂F 5-CH₃ Cl F A-3474. H CH₂F5-OCH₃ Cl F A-3475. H CHF₂ 3-F Cl F A-3476. H CHF₂ 3-CH₃ Cl F A-3477. HCHF₂ 3-OCH₃ Cl F A-3478. H CHF₂ 5-F Cl F A-3479. H CHF₂ 5-CH₃ Cl FA-3480. H CHF₂ 5-OCH₃ Cl F A-3481. H CF₃ 3-F Cl F A-3482. H CF₃ 3-CH₃ ClF A-3483. H CF₃ 3-OCH₃ Cl F A-3484. H CF₃ 5-F Cl F A-3485. H CF₃ 5-CH₃Cl F A-3486. H CF₃ 5-OCH₃ Cl F A-3487. H OCH₂F 3-F Cl F A-3488. H OCH₂F3-CH₃ Cl F A-3489. H OCH₂F 3-OCH₃ Cl F A-3490. H OCH₂F 5-F Cl F A-3491.H OCH₂F 5-CH₃ Cl F A-3492. H OCH₂F 5-OCH₃ Cl F A-3493. H OCHF₂ 3-F Cl FA-3494. H OCHF₂ 3-CH₃ Cl F A-3495. H OCHF₂ 3-OCH₃ Cl F A-3496. H OCHF₂5-F Cl F A-3497. H OCHF₂ 5-CH₃ Cl F A-3498. H OCHF₂ 5-OCH₃ Cl F A-3499.H OCF₃ 3-F Cl F A-3500. H OCF₃ 3-CH₃ Cl F A-3501. H OCF₃ 3-OCH₃ Cl FA-3502. H OCF₃ 5-F Cl F A-3503. H OCF₃ 5-CH₃ Cl F A-3504. H OCF₃ 5-OCH₃Cl F A-3505. F F 3-F Cl F A-3506. F F 3-CH₃ Cl F A-3507. F F 3-OCH₃ Cl FA-3508. F F 5-F Cl F A-3509. F F 5-CH₃ Cl F A-3510. F F 5-OCH₃ Cl FA-3511. F CH₃ 3-F Cl F A-3512. F CH₃ 3-CH₃ Cl F A-3513. F CH₃ 3-OCH₃ ClF A-3514. F CH₃ 5-F Cl F A-3515. F CH₃ 5-CH₃ Cl F A-3516. F CH₃ 5-OCH₃Cl F A-3517. F OCH₃ 3-F Cl F A-3518. F OCH₃ 3-CH₃ Cl F A-3519. F OCH₃3-OCH₃ Cl F A-3520. F OCH₃ 5-F Cl F A-3521. F OCH₃ 5-CH₃ Cl F A-3522. FOCH₃ 5-OCH₃ Cl F A-3523. F CN 3-F Cl F A-3524. F CN 3-CH₃ Cl F A-3525. FCN 3-OCH₃ Cl F A-3526. F CN 5-F Cl F A-3527. F CN 5-CH₃ Cl F A-3528. FCN 5-OCH₃ Cl F A-3529. F CH₂F 3-F Cl F A-3530. F CH₂F 3-CH₃ Cl F A-3531.F CH₂F 3-OCH₃ Cl F A-3532. F CH₂F 5-F Cl F A-3533. F CH₂F 5-CH₃ Cl FA-3534. F CH₂F 5-OCH₃ Cl F A-3535. F CHF₂ 3-F Cl F A-3536. F CHF₂ 3-CH₃Cl F A-3537. F CHF₂ 3-OCH₃ Cl F A-3538. F CHF₂ 5-F Cl F A-3539. F CHF₂5-CH₃ Cl F A-3540. F CHF₂ 5-OCH₃ Cl F A-3541. F CF₃ 3-F Cl F A-3542. FCF₃ 3-CH₃ Cl F A-3543. F CF₃ 3-OCH₃ Cl F A-3544. F CF₃ 5-F Cl F A-3545.F CF₃ 5-CH₃ Cl F A-3546. F CF₃ 5-OCH₃ Cl F A-3547. F OCH₂F 3-F Cl FA-3548. F OCH₂F 3-CH₃ Cl F A-3549. F OCH₂F 3-OCH₃ Cl F A-3550. F OCH₂F5-F Cl F A-3551. F OCH₂F 5-CH₃ Cl F A-3552. F OCH₂F 5-OCH₃ Cl F A-3553.F OCHF₂ 3-F Cl F A-3554. F OCHF₂ 3-CH₃ Cl F A-3555. F OCHF₂ 3-OCH₃ Cl FA-3556. F OCHF₂ 5-F Cl F A-3557. F OCHF₂ 5-CH₃ Cl F A-3558. F OCHF₂5-OCH₃ Cl F A-3559. F OCF₃ 3-F Cl F A-3560. F OCF₃ 3-CH₃ Cl F A-3561. FOCF₃ 3-OCH₃ Cl F A-3562. F OCF₃ 5-F Cl F A-3563. F OCF₃ 5-CH₃ Cl FA-3564. F OCF₃ 5-OCH₃ Cl F A-3565. CH₃ F 3-F Cl F A-3566. CH₃ F 3-CH₃ ClF A-3567. CH₃ F 3-OCH₃ Cl F A-3568. CH₃ F 5-F Cl F A-3569. CH₃ F 5-CH₃Cl F A-3570. CH₃ F 5-OCH₃ Cl F A-3571. CH₃ CH₃ 3-F Cl F A-3572. CH₃ CH₃3-CH₃ Cl F A-3573. CH₃ CH₃ 3-OCH₃ Cl F A-3574. CH₃ CH₃ 5-F Cl F A-3575.CH₃ CH₃ 5-CH₃ Cl F A-3576. CH₃ CH₃ 5-OCH₃ Cl F A-3577. CH₃ OCH₃ 3-F Cl FA-3578. CH₃ OCH₃ 3-CH₃ Cl F A-3579. CH₃ OCH₃ 3-OCH₃ Cl F A-3580. CH₃OCH₃ 5-F Cl F A-3581. CH₃ OCH₃ 5-CH₃ Cl F A-3582. CH₃ OCH₃ 5-OCH₃ Cl FA-3583. CH₃ CN 3-F Cl F A-3584. CH₃ CN 3-CH₃ Cl F A-3585. CH₃ CN 3-OCH₃Cl F A-3586. CH₃ CN 5-F Cl F A-3587. CH₃ CN 5-CH₃ Cl F A-3588. CH₃ CN5-OCH₃ Cl F A-3589. CH₃ CH₂F 3-F Cl F A-3590. CH₃ CH₂F 3-CH₃ Cl FA-3591. CH₃ CH₂F 3-OCH₃ Cl F A-3592. CH₃ CH₂F 5-F Cl F A-3593. CH₃ CH₂F5-CH₃ Cl F A-3594. CH₃ CH₂F 5-OCH₃ Cl F A-3595. CH₃ CHF₂ 3-F Cl FA-3596. CH₃ CHF₂ 3-CH₃ Cl F A-3597. CH₃ CHF₂ 3-OCH₃ Cl F A-3598. CH₃CHF₂ 5-F Cl F A-3599. CH₃ CHF₂ 5-CH₃ Cl F A-3600. CH₃ CHF₂ 5-OCH₃ Cl FA-3601. CH₃ CF₃ 3-F Cl F A-3602. CH₃ CF₃ 3-CH₃ Cl F A-3603. CH₃ CF₃3-OCH₃ Cl F A-3604. CH₃ CF₃ 5-F Cl F A-3605. CH₃ CF₃ 5-CH₃ Cl F A-3606.CH₃ CF₃ 5-OCH₃ Cl F A-3607. CH₃ OCH₂F 3-F Cl F A-3608. CH₃ OCH₂F 3-CH₃Cl F A-3609. CH₃ OCH₂F 3-OCH₃ Cl F A-3610. CH₃ OCH₂F 5-F Cl F A-3611.CH₃ OCH₂F 5-CH₃ Cl F A-3612. CH₃ OCH₂F 5-OCH₃ Cl F A-3613. CH₃ OCHF₂ 3-FCl F A-3614. CH₃ OCHF₂ 3-CH₃ Cl F A-3615. CH₃ OCHF₂ 3-OCH₃ Cl F A-3616.CH₃ OCHF₂ 5-F Cl F A-3617. CH₃ OCHF₂ 5-CH₃ Cl F A-3618. CH₃ OCHF₂ 5-OCH₃Cl F A-3619. CH₃ OCF₃ 3-F Cl F A-3620. CH₃ OCF₃ 3-CH₃ Cl F A-3621. CH₃OCF₃ 3-OCH₃ Cl F A-3622. CH₃ OCF₃ 5-F Cl F A-3623. CH₃ OCF₃ 5-CH₃ Cl FA-3624. CH₃ OCF₃ 5-OCH₃ Cl F A-3625. OCH₃ F 3-F Cl F A-3626. OCH₃ F3-CH₃ Cl F A-3627. OCH₃ F 3-OCH₃ Cl F A-3628. OCH₃ F 5-F Cl F A-3629.OCH₃ F 5-CH₃ Cl F A-3630. OCH₃ F 5-OCH₃ Cl F A-3631. OCH₃ CH₃ 3-F Cl FA-3632. OCH₃ CH₃ 3-CH₃ Cl F A-3633. OCH₃ CH₃ 3-OCH₃ Cl F A-3634. OCH₃CH₃ 5-F Cl F A-3635. OCH₃ CH₃ 5-CH₃ Cl F A-3636. OCH₃ CH₃ 5-OCH₃ Cl FA-3637. OCH₃ OCH₃ 3-F Cl F A-3638. OCH₃ OCH₃ 3-CH₃ Cl F A-3639. OCH₃OCH₃ 3-OCH₃ Cl F A-3640. OCH₃ OCH₃ 5-F Cl F A-3641. OCH₃ OCH₃ 5-CH₃ Cl FA-3642. OCH₃ OCH₃ 5-OCH₃ Cl F A-3643. OCH₃ CN 3-F Cl F A-3644. OCH₃ CN3-CH₃ Cl F A-3645. OCH₃ CN 3-OCH₃ Cl F A-3646. OCH₃ CN 5-F Cl F A-3647.OCH₃ CN 5-CH₃ Cl F A-3648. OCH₃ CN 5-OCH₃ Cl F A-3649. OCH₃ CH₂F 3-F ClF A-3650. OCH₃ CH₂F 3-CH₃ Cl F A-3651. OCH₃ CH₂F 3-OCH₃ Cl F A-3652.OCH₃ CH₂F 5-F Cl F A-3653. OCH₃ CH₂F 5-CH₃ Cl F A-3654. OCH₃ CH₂F 5-OCH₃Cl F A-3655. OCH₃ CHF₂ 3-F Cl F A-3656. OCH₃ CHF₂ 3-CH₃ Cl F A-3657.OCH₃ CHF₂ 3-OCH₃ Cl F A-3658. OCH₃ CHF₂ 5-F Cl F A-3659. OCH₃ CHF₂ 5-CH₃Cl F A-3660. OCH₃ CHF₂ 5-OCH₃ Cl F A-3661. OCH₃ CF₃ 3-F Cl F A-3662.OCH₃ CF₃ 3-CH₃ Cl F A-3663. OCH₃ CF₃ 3-OCH₃ Cl F A-3664. OCH₃ CF₃ 5-F ClF A-3665. OCH₃ CF₃ 5-CH₃ Cl F A-3666. OCH₃ CF₃ 5-OCH₃ Cl F A-3667. OCH₃OCH₂F 3-F Cl F A-3668. OCH₃ OCH₂F 3-CH₃ Cl F A-3669. OCH₃ OCH₂F 3-OCH₃Cl F A-3670. OCH₃ OCH₂F 5-F Cl F A-3671. OCH₃ OCH₂F 5-CH₃ Cl F A-3672.OCH₃ OCH₂F 5-OCH₃ Cl F A-3673. OCH₃ OCHF₂ 3-F Cl F A-3674. OCH₃ OCHF₂3-CH₃ Cl F A-3675. OCH₃ OCHF₂ 3-OCH₃ Cl F A-3676. OCH₃ OCHF₂ 5-F Cl FA-3677. OCH₃ OCHF₂ 5-CH₃ Cl F A-3678. OCH₃ OCHF₂ 5-OCH₃ Cl F A-3679.OCH₃ OCF₃ 3-F Cl F A-3680. OCH₃ OCF₃ 3-CH₃ Cl F A-3681. OCH₃ OCF₃ 3-OCH₃Cl F A-3682. OCH₃ OCF₃ 5-F Cl F A-3683. OCH₃ OCF₃ 5-CH₃ Cl F A-3684.OCH₃ OCF₃ 5-OCH₃ Cl F A-3685. CH₂F F 3-F Cl F A-3686. CH₂F F 3-CH₃ Cl FA-3687. CH₂F F 3-OCH₃ Cl F A-3688. CH₂F F 5-F Cl F A-3689. CH₂F F 5-CH₃Cl F A-3690. CH₂F F 5-OCH₃ Cl F A-3691. CH₂F CH₃ 3-F Cl F A-3692. CH₂FCH₃ 3-CH₃ Cl F A-3693. CH₂F CH₃ 3-OCH₃ Cl F A-3694. CH₂F CH₃ 5-F Cl FA-3695. CH₂F CH₃ 5-CH₃ Cl F A-3696. CH₂F CH₃ 5-OCH₃ Cl F A-3697. CH₂FOCH₃ 3-F Cl F A-3698. CH₂F OCH₃ 3-CH₃ Cl F A-3699. CH₂F OCH₃ 3-OCH₃ Cl FA-3700. CH₂F OCH₃ 5-F Cl F A-3701. CH₂F OCH₃ 5-CH₃ Cl F A-3702. CH₂FOCH₃ 5-OCH₃ Cl F A-3703. CH₂F CN 3-F Cl F A-3704. CH₂F CN 3-CH₃ Cl FA-3705. CH₂F CN 3-OCH₃ Cl F A-3706. CH₂F CN 5-F Cl F A-3707. CH₂F CN5-CH₃ Cl F A-3708. CH₂F CN 5-OCH₃ Cl F A-3709. CH₂F CH₂F 3-F Cl FA-3710. CH₂F CH₂F 3-CH₃ Cl F A-3711. CH₂F CH₂F 3-OCH₃ Cl F A-3712. CH₂FCH₂F 5-F Cl F A-3713. CH₂F CH₂F 5-CH₃ Cl F A-3714. CH₂F CH₂F 5-OCH₃ Cl FA-3715. CH₂F CHF₂ 3-F Cl F A-3716. CH₂F CHF₂ 3-CH₃ Cl F A-3717. CH₂FCHF₂ 3-OCH₃ Cl F A-3718. CH₂F CHF₂ 5-F Cl F A-3719. CH₂F CHF₂ 5-CH₃ Cl FA-3720. CH₂F CHF₂ 5-OCH₃ Cl F A-3721. CH₂F CF₃ 3-F Cl F A-3722. CH₂F CF₃3-CH₃ Cl F A-3723. CH₂F CF₃ 3-OCH₃ Cl F A-3724. CH₂F CF₃ 5-F Cl FA-3725. CH₂F CF₃ 5-CH₃ Cl F A-3726. CH₂F CF₃ 5-OCH₃ Cl F A-3727. CH₂FOCH₂F 3-F Cl F A-3728. CH₂F OCH₂F 3-CH₃ Cl F A-3729. CH₂F OCH₂F 3-OCH₃Cl F A-3730. CH₂F OCH₂F 5-F Cl F A-3731. CH₂F OCH₂F 5-CH₃ Cl F A-3732.CH₂F OCH₂F 5-OCH₃ Cl F A-3733. CH₂F OCHF₂ 3-F Cl F A-3734. CH₂F OCHF₂3-CH₃ Cl F A-3735. CH₂F OCHF₂ 3-OCH₃ Cl F A-3736. CH₂F OCHF₂ 5-F Cl FA-3737. CH₂F OCHF₂ 5-CH₃ Cl F A-3738. CH₂F OCHF₂ 5-OCH₃ Cl F A-3739.CH₂F OCF₃ 3-F Cl F A-3740. CH₂F OCF₃ 3-CH₃ Cl F A-3741. CH₂F OCF₃ 3-OCH₃Cl F A-3742. CH₂F OCF₃ 5-F Cl F A-3743. CH₂F OCF₃ 5-CH₃ Cl F A-3744.CH₂F OCF₃ 5-OCH₃ Cl F A-3745. CHF₂ F 3-F Cl F A-3746. CHF₂ F 3-CH₃ Cl FA-3747. CHF₂ F 3-OCH₃ Cl F A-3748. CHF₂ F 5-F Cl F A-3749. CHF₂ F 5-CH₃Cl F A-3750. CHF₂ F 5-OCH₃ Cl F A-3751. CHF₂ CH₃ 3-F Cl F A-3752. CHF₂CH₃ 3-CH₃ Cl F A-3753. CHF₂ CH₃ 3-OCH₃ Cl F A-3754. CHF₂ CH₃ 5-F Cl FA-3755. CHF₂ CH₃ 5-CH₃ Cl F A-3756. CHF₂ CH₃ 5-OCH₃ Cl F A-3757. CHF₂OCH₃ 3-F Cl F A-3758. CHF₂ OCH₃ 3-CH₃ Cl F A-3759. CHF₂ OCH₃ 3-OCH₃ Cl FA-3760. CHF₂ OCH₃ 5-F Cl F A-3761. CHF₂ OCH₃ 5-CH₃ Cl F A-3762. CHF₂OCH₃ 5-OCH₃ Cl F A-3763. CHF₂ CN 3-F Cl F A-3764. CHF₂ CN 3-CH₃ Cl FA-3765. CHF₂ CN 3-OCH₃ Cl F A-3766. CHF₂ CN 5-F Cl F A-3767. CHF₂ CN5-CH₃ Cl F A-3768. CHF₂ CN 5-OCH₃ Cl F A-3769. CHF₂ CH₂F 3-F Cl FA-3770. CHF₂ CH₂F 3-CH₃ Cl F A-3771. CHF₂ CH₂F 3-OCH₃ Cl F A-3772. CHF₂CH₂F 5-F Cl F A-3773. CHF₂ CH₂F 5-CH₃ Cl F A-3774. CHF₂ CH₂F 5-OCH₃ Cl FA-3775. CHF₂ CHF₂ 3-F Cl F A-3776. CHF₂ CHF₂ 3-CH₃ Cl F A-3777. CHF₂CHF₂ 3-OCH₃ Cl F A-3778. CHF₂ CHF₂ 5-F Cl F A-3779. CHF₂ CHF₂ 5-CH₃ Cl FA-3780. CHF₂ CHF₂ 5-OCH₃ Cl F A-3781. CHF₂ CF₃ 3-F Cl F A-3782. CHF₂ CF₃3-CH₃ Cl F A-3783. CHF₂ CF₃ 3-OCH₃ Cl F A-3784. CHF₂ CF₃ 5-F Cl FA-3785. CHF₂ CF₃ 5-CH₃ Cl F A-3786. CHF₂ CF₃ 5-OCH₃ Cl F A-3787. CHF₂OCH₂F 3-F Cl F A-3788. CHF₂ OCH₂F 3-CH₃ Cl F A-3789. CHF₂ OCH₂F 3-OCH₃Cl F A-3790. CHF₂ OCH₂F 5-F Cl F A-3791. CHF₂ OCH₂F 5-CH₃ Cl F A-3792.CHF₂ OCH₂F 5-OCH₃ Cl F A-3793. CHF₂ OCHF₂ 3-F Cl F A-3794. CHF₂ OCHF₂3-CH₃ Cl F A-3795. CHF₂ OCHF₂ 3-OCH₃ Cl F A-3796. CHF₂ OCHF₂ 5-F Cl FA-3797. CHF₂ OCHF₂ 5-CH₃ Cl F A-3798. CHF₂ OCHF₂ 5-OCH₃ Cl F A-3799.CHF₂ OCF₃ 3-F Cl F A-3800. CHF₂ OCF₃ 3-CH₃ Cl F A-3801. CHF₂ OCF₃ 3-OCH₃Cl F A-3802. CHF₂ OCF₃ 5-F Cl F A-3803. CHF₂ OCF₃ 5-CH₃ Cl F A-3804.CHF₂ OCF₃ 5-OCH₃ Cl F A-3805. CF₃ F 3-F Cl F A-3806. CF₃ F 3-CH₃ Cl FA-3807. CF₃ F 3-OCH₃ Cl F A-3808. CF₃ F 5-F Cl F A-3809. CF₃ F 5-CH₃ ClF A-3810. CF₃ F 5-OCH₃ Cl F A-3811. CF₃ CH₃ 3-F Cl F A-3812. CF₃ CH₃3-CH₃ Cl F A-3813. CF₃ CH₃ 3-OCH₃ Cl F A-3814. CF₃ CH₃ 5-F Cl F A-3815.CF₃ CH₃ 5-CH₃ Cl F A-3816. CF₃ CH₃ 5-OCH₃ Cl F A-3817. CF₃ OCH₃ 3-F Cl FA-3818. CF₃ OCH₃ 3-CH₃ Cl F A-3819. CF₃ OCH₃ 3-OCH₃ Cl F A-3820. CF₃OCH₃ 5-F Cl F A-3821. CF₃ OCH₃ 5-CH₃ Cl F A-3822. CF₃ OCH₃ 5-OCH₃ Cl FA-3823. CF₃ CN 3-F Cl F A-3824. CF₃ CN 3-CH₃ Cl F A-3825. CF₃ CN 3-OCH₃Cl F A-3826. CF₃ CN 5-F Cl F A-3827. CF₃ CN 5-CH₃ Cl F A-3828. CF₃ CN5-OCH₃ Cl F A-3829. CF₃ CH₂F 3-F Cl F A-3830. CF₃ CH₂F 3-CH₃ Cl FA-3831. CF₃ CH₂F 3-OCH₃ Cl F A-3832. CF₃ CH₂F 5-F Cl F A-3833. CF₃ CH₂F5-CH₃ Cl F A-3834. CF₃ CH₂F 5-OCH₃ Cl F A-3835. CF₃ CHF₂ 3-F Cl FA-3836. CF₃ CHF₂ 3-CH₃ Cl F A-3837. CF₃ CHF₂ 3-OCH₃ Cl F A-3838. CF₃CHF₂ 5-F Cl F A-3839. CF₃ CHF₂ 5-CH₃ Cl F A-3840. CF₃ CHF₂ 5-OCH₃ Cl FA-3841. CF₃ CF₃ 3-F Cl F A-3842. CF₃ CF₃ 3-CH₃ Cl F A-3843. CF₃ CF₃3-OCH₃ Cl F A-3844. CF₃ CF₃ 5-F Cl F A-3845. CF₃ CF₃ 5-CH₃ Cl F A-3846.CF₃ CF₃ 5-OCH₃ Cl F A-3847. CF₃ OCH₂F 3-F Cl F A-3848. CF₃ OCH₂F 3-CH₃Cl F A-3849. CF₃ OCH₂F 3-OCH₃ Cl F A-3850. CF₃ OCH₂F 5-F Cl F A-3851.CF₃ OCH₂F 5-CH₃ Cl F A-3852. CF₃ OCH₂F 5-OCH₃ Cl F A-3853. CF₃ OCHF₂ 3-FCl F A-3854. CF₃ OCHF₂ 3-CH₃ Cl F A-3855. CF₃ OCHF₂ 3-OCH₃ Cl F A-3856.CF₃ OCHF₂ 5-F Cl F A-3857. CF₃ OCHF₂ 5-CH₃ Cl F A-3858. CF₃ OCHF₂ 5-OCH₃Cl F A-3859. CF₃ OCF₃ 3-F Cl F A-3860. CF₃ OCF₃ 3-CH₃ Cl F A-3861. CF₃OCF₃ 3-OCH₃ Cl F A-3862. CF₃ OCF₃ 5-F Cl F A-3863. CF₃ OCF₃ 5-CH₃ Cl FA-3864. CF₃ OCF₃ 5-OCH₃ Cl F A-3865. OCH₂F F 3-F Cl F A-3866. OCH₂F F3-CH₃ Cl F A-3867. OCH₂F F 3-OCH₃ Cl F A-3868. OCH₂F F 5-F Cl F A-3869.OCH₂F F 5-CH₃ Cl F A-3870. OCH₂F F 5-OCH₃ Cl F A-3871. OCH₂F CH₃ 3-F ClF A-3872. OCH₂F CH₃ 3-CH₃ Cl F A-3873. OCH₂F CH₃ 3-OCH₃ Cl F A-3874.OCH₂F CH₃ 5-F Cl F A-3875. OCH₂F CH₃ 5-CH₃ Cl F A-3876. OCH₂F CH₃ 5-OCH₃Cl F A-3877. OCH₂F OCH₃ 3-F Cl F A-3878. OCH₂F OCH₃ 3-CH₃ Cl F A-3879.OCH₂F OCH₃ 3-OCH₃ Cl F A-3880. OCH₂F OCH₃ 5-F Cl F A-3881. OCH₂F OCH₃5-CH₃ Cl F A-3882. OCH₂F OCH₃ 5-OCH₃ Cl F A-3883. OCH₂F CN 3-F Cl FA-3884. OCH₂F CN 3-CH₃ Cl F A-3885. OCH₂F CN 3-OCH₃ Cl F A-3886. OCH₂FCN 5-F Cl F A-3887. OCH₂F CN 5-CH₃ Cl F A-3888. OCH₂F CN 5-OCH₃ Cl FA-3889. OCH₂F CH₂F 3-F Cl F A-3890. OCH₂F CH₂F 3-CH₃ Cl F A-3891. OCH₂FCH₂F 3-OCH₃ Cl F A-3892. OCH₂F CH₂F 5-F Cl F A-3893. OCH₂F CH₂F 5-CH₃ ClF A-3894. OCH₂F CH₂F 5-OCH₃ Cl F A-3895. OCH₂F CHF₂ 3-F Cl F A-3896.OCH₂F CHF₂ 3-CH₃ Cl F A-3897. OCH₂F CHF₂ 3-OCH₃ Cl F A-3898. OCH₂F CHF₂5-F Cl F A-3899. OCH₂F CHF₂ 5-CH₃ Cl F A-3900. OCH₂F CHF₂ 5-OCH₃ Cl FA-3901. OCH₂F CF₃ 3-F Cl F A-3902. OCH₂F CF₃ 3-CH₃ Cl F A-3903. OCH₂FCF₃ 3-OCH₃ Cl F A-3904. OCH₂F CF₃ 5-F Cl F A-3905. OCH₂F CF₃ 5-CH₃ Cl FA-3906. OCH₂F CF₃ 5-OCH₃ Cl F A-3907. OCH₂F OCH₂F 3-F Cl F A-3908. OCH₂FOCH₂F 3-CH₃ Cl F A-3909. OCH₂F OCH₂F 3-OCH₃ Cl F A-3910. OCH₂F OCH₂F 5-FCl F A-3911. OCH₂F OCH₂F 5-CH₃ Cl F A-3912. OCH₂F OCH₂F 5-OCH₃ Cl FA-3913. OCH₂F OCHF₂ 3-F Cl F A-3914. OCH₂F OCHF₂ 3-CH₃ Cl F A-3915.OCH₂F OCHF₂ 3-OCH₃ Cl F A-3916. OCH₂F OCHF₂ 5-F Cl F A-3917. OCH₂F OCHF₂5-CH₃ Cl F A-3918. OCH₂F OCHF₂ 5-OCH₃ Cl F A-3919. OCH₂F OCF₃ 3-F Cl FA-3920. OCH₂F OCF₃ 3-CH₃ Cl F A-3921. OCH₂F OCF₃ 3-OCH₃ Cl F A-3922.OCH₂F OCF₃ 5-F Cl F A-3923. OCH₂F OCF₃ 5-CH₃ Cl F A-3924. OCH₂F OCF₃5-OCH₃ Cl F A-3925. OCHF₂ F 3-F Cl F A-3926. OCHF₂ F 3-CH₃ Cl F A-3927.OCHF₂ F 3-OCH₃ Cl F A-3928. OCHF₂ F 5-F Cl F A-3929. OCHF₂ F 5-CH₃ Cl FA-3930. OCHF₂ F 5-OCH₃ Cl F A-3931. OCHF₂ CH₃ 3-F Cl F A-3932. OCHF₂ CH₃3-CH₃ Cl F A-3933. OCHF₂ CH₃ 3-OCH₃ Cl F A-3934. OCHF₂ CH₃ 5-F Cl FA-3935. OCHF₂ CH₃ 5-CH₃ Cl F A-3936. OCHF₂ CH₃ 5-OCH₃ Cl F A-3937. OCHF₂OCH₃ 3-F Cl F A-3938. OCHF₂ OCH₃ 3-CH₃ Cl F A-3939. OCHF₂ OCH₃ 3-OCH₃ ClF A-3940. OCHF₂ OCH₃ 5-F Cl F A-3941. OCHF₂ OCH₃ 5-CH₃ Cl F A-3942.OCHF₂ OCH₃ 5-OCH₃ Cl F A-3943. OCHF₂ CN 3-F Cl F A-3944. OCHF₂ CN 3-CH₃Cl F A-3945. OCHF₂ CN 3-OCH₃ Cl F A-3946. OCHF₂ CN 5-F Cl F A-3947.OCHF₂ CN 5-CH₃ Cl F A-3948. OCHF₂ CN 5-OCH₃ Cl F A-3949. OCHF₂ CH₂F 3-FCl F A-3950. OCHF₂ CH₂F 3-CH₃ Cl F A-3951. OCHF₂ CH₂F 3-OCH₃ Cl FA-3952. OCHF₂ CH₂F 5-F Cl F A-3953. OCHF₂ CH₂F 5-CH₃ Cl F A-3954. OCHF₂CH₂F 5-OCH₃ Cl F A-3955. OCHF₂ CHF₂ 3-F Cl F A-3956. OCHF₂ CHF₂ 3-CH₃ ClF A-3957. OCHF₂ CHF₂ 3-OCH₃ Cl F A-3958. OCHF₂ CHF₂ 5-F Cl F A-3959.OCHF₂ CHF₂ 5-CH₃ Cl F A-3960. OCHF₂ CHF₂ 5-OCH₃ Cl F A-3961. OCHF₂ CF₃3-F Cl F A-3962. OCHF₂ CF₃ 3-CH₃ Cl F A-3963. OCHF₂ CF₃ 3-OCH₃ Cl FA-3964. OCHF₂ CF₃ 5-F Cl F A-3965. OCHF₂ CF₃ 5-CH₃ Cl F A-3966. OCHF₂CF₃ 5-OCH₃ Cl F A-3967. OCHF₂ OCH₂F 3-F Cl F A-3968. OCHF₂ OCH₂F 3-CH₃Cl F A-3969. OCHF₂ OCH₂F 3-OCH₃ Cl F A-3970. OCHF₂ OCH₂F 5-F Cl FA-3971. OCHF₂ OCH₂F 5-CH₃ Cl F A-3972. OCHF₂ OCH₂F 5-OCH₃ Cl F A-3973.OCHF₂ OCHF₂ 3-F Cl F A-3974. OCHF₂ OCHF₂ 3-CH₃ Cl F A-3975. OCHF₂ OCHF₂3-OCH₃ Cl F A-3976. OCHF₂ OCHF₂ 5-F Cl F A-3977. OCHF₂ OCHF₂ 5-CH₃ Cl FA-3978. OCHF₂ OCHF₂ 5-OCH₃ Cl F A-3979. OCHF₂ OCF₃ 3-F Cl F A-3980.OCHF₂ OCF₃ 3-CH₃ Cl F A-3981. OCHF₂ OCF₃ 3-OCH₃ Cl F A-3982. OCHF₂ OCF₃5-F Cl F A-3983. OCHF₂ OCF₃ 5-CH₃ Cl F A-3984. OCHF₂ OCF₃ 5-OCH₃ Cl FA-3985. OCF₃ F 3-F Cl F A-3986. OCF₃ F 3-CH₃ Cl F A-3987. OCF₃ F 3-OCH₃Cl F A-3988. OCF₃ F 5-F Cl F A-3989. OCF₃ F 5-CH₃ Cl F A-3990. OCF₃ F5-OCH₃ Cl F A-3991. OCF₃ CH₃ 3-F Cl F A-3992. OCF₃ CH₃ 3-CH₃ Cl FA-3993. OCF₃ CH₃ 3-OCH₃ Cl F A-3994. OCF₃ CH₃ 5-F Cl F A-3995. OCF₃ CH₃5-CH₃ Cl F A-3996. OCF₃ CH₃ 5-OCH₃ Cl F A-3997. OCF₃ OCH₃ 3-F Cl FA-3998. OCF₃ OCH₃ 3-CH₃ Cl F A-3999. OCF₃ OCH₃ 3-OCH₃ Cl F A-4000. OCF₃OCH₃ 5-F Cl F A-4001. OCF₃ OCH₃ 5-CH₃ Cl F A-4002. OCF₃ OCH₃ 5-OCH₃ Cl FA-4003. OCF₃ CN 3-F Cl F A-4004. OCF₃ CN 3-CH₃ Cl F A-4005. OCF₃ CN3-OCH₃ Cl F A-4006. OCF₃ CN 5-F Cl F A-4007. OCF₃ CN 5-CH₃ Cl F A-4008.OCF₃ CN 5-OCH₃ Cl F A-4009. OCF₃ CH₂F 3-F Cl F A-4010. OCF₃ CH₂F 3-CH₃Cl F A-4011. OCF₃ CH₂F 3-OCH₃ Cl F A-4012. OCF₃ CH₂F 5-F Cl F A-4013.OCF₃ CH₂F 5-CH₃ Cl F A-4014. OCF₃ CH₂F 5-OCH₃ Cl F A-4015. OCF₃ CHF₂ 3-FCl F A-4016. OCF₃ CHF₂ 3-CH₃ Cl F A-4017. OCF₃ CHF₂ 3-OCH₃ Cl F A-4018.OCF₃ CHF₂ 5-F Cl F A-4019. OCF₃ CHF₂ 5-CH₃ Cl F A-4020. OCF₃ CHF₂ 5-OCH₃Cl F A-4021. OCF₃ CF₃ 3-F Cl F A-4022. OCF₃ CF₃ 3-CH₃ Cl F A-4023. OCF₃CF₃ 3-OCH₃ Cl F A-4024. OCF₃ CF₃ 5-F Cl F A-4025. OCF₃ CF₃ 5-CH₃ Cl FA-4026. OCF₃ CF₃ 5-OCH₃ Cl F A-4027. OCF₃ OCH₂F 3-F Cl F A-4028. OCF₃OCH₂F 3-CH₃ Cl F A-4029. OCF₃ OCH₂F 3-OCH₃ Cl F A-4030. OCF₃ OCH₂F 5-FCl F A-4031. OCF₃ OCH₂F 5-CH₃ Cl F A-4032. OCF₃ OCH₂F 5-OCH₃ Cl FA-4033. OCF₃ OCHF₂ 3-F Cl F A-4034. OCF₃ OCHF₂ 3-CH₃ Cl F A-4035. OCF₃OCHF₂ 3-OCH₃ Cl F A-4036. OCF₃ OCHF₂ 5-F Cl F A-4037. OCF₃ OCHF₂ 5-CH₃Cl F A-4038. OCF₃ OCHF₂ 5-OCH₃ Cl F A-4039. OCF₃ OCF₃ 3-F Cl F A-4040.OCF₃ OCF₃ 3-CH₃ Cl F A-4041. OCF₃ OCF₃ 3-OCH₃ Cl F A-4042. OCF₃ OCF₃ 5-FCl F A-4043. OCF₃ OCF₃ 5-CH₃ Cl F A-4044. OCF₃ OCF₃ 5-OCH₃ Cl F

TABLE B Example No. R^(8b) R^(8c) R¹ R² B-1. H H CN H B-2. F H CN H B-3.CH₃ H CN H B-4. OCH₃ H CN H B-5. CN H CN H B-6. CH₂F H CN H B-7. CHF₂ HCN H B-8. CF₃ H CN H B-9. OCH₂F H CN H B-10. OCHF₂ H CN H B-11. OCF₃ HCN H B-12. H 3-F CN H B-13. H 3-CH₃ CN H B-14. H 3-OCH₃ CN H B-15. H 5-FCN H B-16. H 5-CH₃ CN H B-17. H 5-OCH₃ CN H B-18. H 6-F CN H B-19. H6-CH₃ CN H B-20. H 6-OCH₃ CN H B-21. F 3-F CN H B-22. F 3-CH₃ CN H B-23.F 3-OCH₃ CN H B-24. F 5-F CN H B-25. F 5-CH₃ CN H B-26. F 5-OCH₃ CN HB-27. F 6-F CN H B-28. F 6-CH₃ CN H B-29. F 6-OCH₃ CN H B-30. CH₃ 3-F CNH B-31. CH₃ 3-CH₃ CN H B-32. CH₃ 3-OCH₃ CN H B-33. CH₃ 5-F CN H B-34.CH₃ 5-CH₃ CN H B-35. CH₃ 5-OCH₃ CN H B-36. CH₃ 6-F CN H B-37. CH₃ 6-CH₃CN H B-38. CH₃ 6-OCH₃ CN H B-39. OCH₃ 3-F CN H B-40. OCH₃ 3-CH₃ CN HB-41. OCH₃ 3-OCH₃ CN H B-42. OCH₃ 5-F CN H B-43. OCH₃ 5-CH₃ CN H B-44.OCH₃ 5-OCH₃ CN H B-45. OCH₃ 6-F CN H B-46. OCH₃ 6-CH₃ CN H B-47. OCH₃6-OCH₃ CN H B-48. CN 3-F CN H B-49. CN 3-CH₃ CN H B-50. CN 3-OCH₃ CN HB-51. CN 5-F CN H B-52. CN 5-CH₃ CN H B-53. CN 5-OCH₃ CN H B-54. CN 6-FCN H B-55. CN 6-CH₃ CN H B-56. CN 6-OCH₃ CN H B-57. CH₂F 3-F CN H B-58.CH₂F 3-CH₃ CN H B-59. CH₂F 3-OCH₃ CN H B-60. CH₂F 5-F CN H B-61. CH₂F5-CH₃ CN H B-62. CH₂F 5-OCH₃ CN H B-63. CH₂F 6-F CN H B-64. CH₂F 6-CH₃CN H B-65. CH₂F 6-OCH₃ CN H B-66. CHF₂ 3-F CN H B-67. CHF₂ 3-CH₃ CN HB-68. CHF₂ 3-OCH₃ CN H B-69. CHF₂ 5-F CN H B-70. CHF₂ 5-CH₃ CN H B-71.CHF₂ 5-OCH₃ CN H B-72. CHF₂ 6-F CN H B-73. CHF₂ 6-CH₃ CN H B-74. CHF₂6-OCH₃ CN H B-75. CF₃ 3-F CN H B-76. CF₃ 3-CH₃ CN H B-77. CF₃ 3-OCH₃ CNH B-78. CF₃ 5-F CN H B-79. CF₃ 5-CH₃ CN H B-80. CF₃ 5-OCH₃ CN H B-81.CF₃ 6-F CN H B-82. CF₃ 6-CH₃ CN H B-83. CF₃ 6-OCH₃ CN H B-84. OCH₂F 3-FCN H B-85. OCH₂F 3-CH₃ CN H B-86. OCH₂F 3-OCH₃ CN H B-87. OCH₂F 5-F CN HB-88. OCH₂F 5-CH₃ CN H B-89. OCH₂F 5-OCH₃ CN H B-90. OCH₂F 6-F CN HB-91. OCH₂F 6-CH₃ CN H B-92. OCH₂F 6-OCH₃ CN H B-93. OCHF₂ 3-F CN HB-94. OCHF₂ 3-CH₃ CN H B-95. OCHF₂ 3-OCH₃ CN H B-96. OCHF₂ 5-F CN HB-97. OCHF₂ 5-CH₃ CN H B-98. OCHF₂ 5-OCH₃ CN H B-99. OCHF₂ 6-F CN HB-100. OCHF₂ 6-CH₃ CN H B-101. OCHF₂ 6-OCH₃ CN H B-102. OCF₃ 3-F CN HB-103. OCF₃ 3-CH₃ CN H B-104. OCF₃ 3-OCH₃ CN H B-105. OCF₃ 5-F CN HB-106. OCF₃ 5-CH₃ CN H B-107. OCF₃ 5-OCH₃ CN H B-108. OCF₃ 6-F CN HB-109. OCF₃ 6-CH₃ CN H B-110. OCF₃ 6-OCH₃ CN H B-111. H H F H B-112. F HF H B-113. CH₃ H F H B-114. OCH₃ H F H B-115. CN H F H B-116. CH₂F H F HB-117. CHF₂ H F H B-118. CF₃ H F H B-119. OCH₂F H F H B-120. OCHF₂ H F HB-121. OCF₃ H F H B-122. H 3-F F H B-123. H 3-CH₃ F H B-124. H 3-OCH₃ FH B-125. H 5-F F H B-126. H 5-CH₃ F H B-127. H 5-OCH₃ F H B-128. H 6-F FH B-129. H 6-CH₃ F H B-130. H 6-OCH₃ F H B-131. F 3-F F H B-132. F 3-CH₃F H B-133. F 3-OCH₃ F H B-134. F 5-F F H B-135. F 5-CH₃ F H B-136. F5-OCH₃ F H B-137. F 6-F F H B-138. F 6-CH₃ F H B-139. F 6-OCH₃ F HB-140. CH₃ 3-F F H B-141. CH₃ 3-CH₃ F H B-142. CH₃ 3-OCH₃ F H B-143. CH₃5-F F H B-144. CH₃ 5-CH₃ F H B-145. CH₃ 5-OCH₃ F H B-146. CH₃ 6-F F HB-147. CH₃ 6-CH₃ F H B-148. CH₃ 6-OCH₃ F H B-149. OCH₃ 3-F F H B-150.OCH₃ 3-CH₃ F H B-151. OCH₃ 3-OCH₃ F H B-152. OCH₃ 5-F F H B-153. OCH₃5-CH₃ F H B-154. OCH₃ 5-OCH₃ F H B-155. OCH₃ 6-F F H B-156. OCH₃ 6-CH₃ FH B-157. OCH₃ 6-OCH₃ F H B-158. CN 3-F F H B-159. CN 3-CH₃ F H B-160. CN3-OCH₃ F H B-161. CN 5-F F H B-162. CN 5-CH₃ F H B-163. CN 5-OCH₃ F HB-164. CN 6-F F H B-165. CN 6-CH₃ F H B-166. CN 6-OCH₃ F H B-167. CH₂F3-F F H B-168. CH₂F 3-CH₃ F H B-169. CH₂F 3-OCH₃ F H B-170. CH₂F 5-F F HB-171. CH₂F 5-CH₃ F H B-172. CH₂F 5-OCH₃ F H B-173. CH₂F 6-F F H B-174.CH₂F 6-CH₃ F H B-175. CH₂F 6-OCH₃ F H B-176. CHF₂ 3-F F H B-177. CHF₂3-CH₃ F H B-178. CHF₂ 3-OCH₃ F H B-179. CHF₂ 5-F F H B-180. CHF₂ 5-CH₃ FH B-181. CHF₂ 5-OCH₃ F H B-182. CHF₂ 6-F F H B-183. CHF₂ 6-CH₃ F HB-184. CHF₂ 6-OCH₃ F H B-185. CF₃ 3-F F H B-186. CF₃ 3-CH₃ F H B-187.CF₃ 3-OCH₃ F H B-188. CF₃ 5-F F H B-189. CF₃ 5-CH₃ F H B-190. CF₃ 5-OCH₃F H B-191. CF₃ 6-F F H B-192. CF₃ 6-CH₃ F H B-193. CF₃ 6-OCH₃ F H B-194.OCH₂F 3-F F H B-195. OCH₂F 3-CH₃ F H B-196. OCH₂F 3-OCH₃ F H B-197.OCH₂F 5-F F H B-198. OCH₂F 5-CH₃ F H B-199. OCH₂F 5-OCH₃ F H B-200.OCH₂F 6-F F H B-201. OCH₂F 6-CH₃ F H B-202. OCH₂F 6-OCH₃ F H B-203.OCHF₂ 3-F F H B-204. OCHF₂ 3-CH₃ F H B-205. OCHF₂ 3-OCH₃ F H B-206.OCHF₂ 5-F F H B-207. OCHF₂ 5-CH₃ F H B-208. OCHF₂ 5-OCH₃ F H B-209.OCHF₂ 6-F F H B-210. OCHF₂ 6-CH₃ F H B-211. OCHF₂ 6-OCH₃ F H B-212. OCF₃3-F F H B-213. OCF₃ 3-CH₃ F H B-214. OCF₃ 3-OCH₃ F H B-215. OCF₃ 5-F F HB-216. OCF₃ 5-CH₃ F H B-217. OCF₃ 5-OCH₃ F H B-218. OCF₃ 6-F F H B-219.OCF₃ 6-CH₃ F H B-220. OCF₃ 6-OCH₃ F H B-221. H H Cl H B-222. F H Cl HB-223. CH₃ H Cl H B-224. OCH₃ H Cl H B-225. CN H Cl H B-226. CH₂F H Cl HB-227. CHF₂ H Cl H B-228. CF₃ H Cl H B-229. OCH₂F H Cl H B-230. OCHF₂ HCl H B-231. OCF₃ H Cl H B-232. H 3-F Cl H B-233. H 3-CH₃ Cl H B-234. H3-OCH₃ Cl H B-235. H 5-F Cl H B-236. H 5-CH₃ Cl H B-237. H 5-OCH₃ Cl HB-238. H 6-F Cl H B-239. H 6-CH₃ Cl H B-240. H 6-OCH₃ Cl H B-241. F 3-FCl H B-242. F 3-CH₃ Cl H B-243. F 3-OCH₃ Cl H B-244. F 5-F Cl H B-245. F5-CH₃ Cl H B-246. F 5-OCH₃ Cl H B-247. F 6-F Cl H B-248. F 6-CH₃ Cl HB-249. F 6-OCH₃ Cl H B-250. CH₃ 3-F Cl H B-251. CH₃ 3-CH₃ Cl H B-252.CH₃ 3-OCH₃ Cl H B-253. CH₃ 5-F Cl H B-254. CH₃ 5-CH₃ Cl H B-255. CH₃5-OCH₃ Cl H B-256. CH₃ 6-F Cl H B-257. CH₃ 6-CH₃ Cl H B-258. CH₃ 6-OCH₃Cl H B-259. OCH₃ 3-F Cl H B-260. OCH₃ 3-CH₃ Cl H B-261. OCH₃ 3-OCH₃ Cl HB-262. OCH₃ 5-F Cl H B-263. OCH₃ 5-CH₃ Cl H B-264. OCH₃ 5-OCH₃ Cl HB-265. OCH₃ 6-F Cl H B-266. OCH₃ 6-CH₃ Cl H B-267. OCH₃ 6-OCH₃ Cl HB-268. CN 3-F Cl H B-269. CN 3-CH₃ Cl H B-270. CN 3-OCH₃ Cl H B-271. CN5-F Cl H B-272. CN 5-CH₃ Cl H B-273. CN 5-OCH₃ Cl H B-274. CN 6-F Cl HB-275. CN 6-CH₃ Cl H B-276. CN 6-OCH₃ Cl H B-277. CH₂F 3-F Cl H B-278.CH₂F 3-CH₃ Cl H B-279. CH₂F 3-OCH₃ Cl H B-280. CH₂F 5-F Cl H B-281. CH₂F5-CH₃ Cl H B-282. CH₂F 5-OCH₃ Cl H B-283. CH₂F 6-F Cl H B-284. CH₂F6-CH₃ Cl H B-285. CH₂F 6-OCH₃ Cl H B-286. CHF₂ 3-F Cl H B-287. CHF₂3-CH₃ Cl H B-288. CHF₂ 3-OCH₃ Cl H B-289. CHF₂ 5-F Cl H B-290. CHF₂5-CH₃ Cl H B-291. CHF₂ 5-OCH₃ Cl H B-292. CHF₂ 6-F Cl H B-293. CHF₂6-CH₃ Cl H B-294. CHF₂ 6-OCH₃ Cl H B-295. CF₃ 3-F Cl H B-296. CF₃ 3-CH₃Cl H B-297. CF₃ 3-OCH₃ Cl H B-298. CF₃ 5-F Cl H B-299. CF₃ 5-CH₃ Cl HB-300. CF₃ 5-OCH₃ Cl H B-301. CF₃ 6-F Cl H B-302. CF₃ 6-CH₃ Cl H B-303.CF₃ 6-OCH₃ Cl H B-304. OCH₂F 3-F Cl H B-305. OCH₂F 3-CH₃ Cl H B-306.OCH₂F 3-OCH₃ Cl H B-307. OCH₂F 5-F Cl H B-308. OCH₂F 5-CH₃ Cl H B-309.OCH₂F 5-OCH₃ Cl H B-310. OCH₂F 6-F Cl H B-311. OCH₂F 6-CH₃ Cl H B-312.OCH₂F 6-OCH₃ Cl H B-313. OCHF₂ 3-F Cl H B-314. OCHF₂ 3-CH₃ Cl H B-315.OCHF₂ 3-OCH₃ Cl H B-316. OCHF₂ 5-F Cl H B-317. OCHF₂ 5-CH₃ Cl H B-318.OCHF₂ 5-OCH₃ Cl H B-319. OCHF₂ 6-F Cl H B-320. OCHF₂ 6-CH₃ Cl H B-321.OCHF₂ 6-OCH₃ Cl H B-322. OCF₃ 3-F Cl H B-323. OCF₃ 3-CH₃ Cl H B-324.OCF₃ 3-OCH₃ Cl H B-325. OCF₃ 5-F Cl H B-326. OCF₃ 5-CH₃ Cl H B-327. OCF₃5-OCH₃ Cl H B-328. OCF₃ 6-F Cl H B-329. OCF₃ 6-CH₃ Cl H B-330. OCF₃6-OCH₃ Cl H B-331. H H CN F B-332. F H CN F B-333. CH₃ H CN F B-334.OCH₃ H CN F B-335. CN H CN F B-336. CH₂F H CN F B-337. CHF₂ H CN FB-338. CF₃ H CN F B-339. OCH₂F H CN F B-340. OCHF₂ H CN F B-341. OCF₃ HCN F B-342. H 3-F CN F B-343. H 3-CH₃ CN F B-344. H 3-OCH₃ CN F B-345. H5-F CN F B-346. H 5-CH₃ CN F B-347. H 5-OCH₃ CN F B-348. H 6-F CN FB-349. H 6-CH₃ CN F B-350. H 6-OCH₃ CN F B-351. F 3-F CN F B-352. F3-CH₃ CN F B-353. F 3-OCH₃ CN F B-354. F 5-F CN F B-355. F 5-CH₃ CN FB-356. F 5-OCH₃ CN F B-357. F 6-F CN F B-358. F 6-CH₃ CN F B-359. F6-OCH₃ CN F B-360. CH₃ 3-F CN F B-361. CH₃ 3-CH₃ CN F B-362. CH₃ 3-OCH₃CN F B-363. CH₃ 5-F CN F B-364. CH₃ 5-CH₃ CN F B-365. CH₃ 5-OCH₃ CN FB-366. CH₃ 6-F CN F B-367. CH₃ 6-CH₃ CN F B-368. CH₃ 6-OCH₃ CN F B-369.OCH₃ 3-F CN F B-370. OCH₃ 3-CH₃ CN F B-371. OCH₃ 3-OCH₃ CN F B-372. OCH₃5-F CN F B-373. OCH₃ 5-CH₃ CN F B-374. OCH₃ 5-OCH₃ CN F B-375. OCH₃ 6-FCN F B-376. OCH₃ 6-CH₃ CN F B-377. OCH₃ 6-OCH₃ CN F B-378. CN 3-F CN FB-379. CN 3-CH₃ CN F B-380. CN 3-OCH₃ CN F B-381. CN 5-F CN F B-382. CN5-CH₃ CN F B-383. CN 5-OCH₃ CN F B-384. CN 6-F CN F B-385. CN 6-CH₃ CN FB-386. CN 6-OCH₃ CN F B-387. CH₂F 3-F CN F B-388. CH₂F 3-CH₃ CN F B-389.CH₂F 3-OCH₃ CN F B-390. CH₂F 5-F CN F B-391. CH₂F 5-CH₃ CN F B-392. CH₂F5-OCH₃ CN F B-393. CH₂F 6-F CN F B-394. CH₂F 6-CH₃ CN F B-395. CH₂F6-OCH₃ CN F B-396. CHF₂ 3-F CN F B-397. CHF₂ 3-CH₃ CN F B-398. CHF₂3-OCH₃ CN F B-399. CHF₂ 5-F CN F B-400. CHF₂ 5-CH₃ CN F B-401. CHF₂5-OCH₃ CN F B-402. CHF₂ 6-F CN F B-403. CHF₂ 6-CH₃ CN F B-404. CHF₂6-OCH₃ CN F B-405. CF₃ 3-F CN F B-406. CF₃ 3-CH₃ CN F B-407. CF₃ 3-OCH₃CN F B-408. CF₃ 5-F CN F B-409. CF₃ 5-CH₃ CN F B-410. CF₃ 5-OCH₃ CN FB-411. CF₃ 6-F CN F B-412. CF₃ 6-CH₃ CN F B-413. CF₃ 6-OCH₃ CN F B-414.OCH₂F 3-F CN F B-415. OCH₂F 3-CH₃ CN F B-416. OCH₂F 3-OCH₃ CN F B-417.OCH₂F 5-F CN F B-418. OCH₂F 5-CH₃ CN F B-419. OCH₂F 5-OCH₃ CN F B-420.OCH₂F 6-F CN F B-421. OCH₂F 6-CH₃ CN F B-422. OCH₂F 6-OCH₃ CN F B-423.OCHF₂ 3-F CN F B-424. OCHF₂ 3-CH₃ CN F B-425. OCHF₂ 3-OCH₃ CN F B-426.OCHF₂ 5-F CN F B-427. OCHF₂ 5-CH₃ CN F B-428. OCHF₂ 5-OCH₃ CN F B-429.OCHF₂ 6-F CN F B-430. OCHF₂ 6-CH₃ CN F B-431. OCHF₂ 6-OCH₃ CN F B-432.OCF₃ 3-F CN F B-433. OCF₃ 3-CH₃ CN F B-434. OCF₃ 3-OCH₃ CN F B-435. OCF₃5-F CN F B-436. OCF₃ 5-CH₃ CN F B-437. OCF₃ 5-OCH₃ CN F B-438. OCF₃ 6-FCN F B-439. OCF₃ 6-CH₃ CN F B-440. OCF₃ 6-OCH₃ CN F B-441. H H F FB-442. F H F F B-443. CH₃ H F F B-444. OCH₃ H F F B-445. CN H F F B-446.CH₂F H F F B-447. CHF₂ H F F B-448. CF₃ H F F B-449. OCH₂F H F F B-450.OCHF₂ H F F B-451. OCF₃ H F F B-452. H 3-F F F B-453. H 3-CH₃ F F B-454.H 3-OCH₃ F F B-455. H 5-F F F B-456. H 5-CH₃ F F B-457. H 5-OCH₃ F FB-458. H 6-F F F B-459. H 6-CH₃ F F B-460. H 6-OCH₃ F F B-461. F 3-F F FB-462. F 3-CH₃ F F B-463. F 3-OCH₃ F F B-464. F 5-F F F B-465. F 5-CH₃ FF B-466. F 5-OCH₃ F F B-467. F 6-F F F B-468. F 6-CH₃ F F B-469. F6-OCH₃ F F B-470. CH₃ 3-F F F B-471. CH₃ 3-CH₃ F F B-472. CH₃ 3-OCH₃ F FB-473. CH₃ 5-F F F B-474. CH₃ 5-CH₃ F F B-475. CH₃ 5-OCH₃ F F B-476. CH₃6-F F F B-477. CH₃ 6-CH₃ F F B-478. CH₃ 6-OCH₃ F F B-479. OCH₃ 3-F F FB-480. OCH₃ 3-CH₃ F F B-481. OCH₃ 3-OCH₃ F F B-482. OCH₃ 5-F F F B-483.OCH₃ 5-CH₃ F F B-484. OCH₃ 5-OCH₃ F F B-485. OCH₃ 6-F F F B-486. OCH₃6-CH₃ F F B-487. OCH₃ 6-OCH₃ F F B-488. CN 3-F F F B-489. CN 3-CH₃ F FB-490. CN 3-OCH₃ F F B-491. CN 5-F F F B-492. CN 5-CH₃ F F B-493. CN5-OCH₃ F F B-494. CN 6-F F F B-495. CN 6-CH₃ F F B-496. CN 6-OCH₃ F FB-497. CH₂F 3-F F F B-498. CH₂F 3-CH₃ F F B-499. CH₂F 3-OCH₃ F F B-500.CH₂F 5-F F F B-501. CH₂F 5-CH₃ F F B-502. CH₂F 5-OCH₃ F F B-503. CH₂F6-F F F B-504. CH₂F 6-CH₃ F F B-505. CH₂F 6-OCH₃ F F B-506. CHF₂ 3-F F FB-507. CHF₂ 3-CH₃ F F B-508. CHF₂ 3-OCH₃ F F B-509. CHF₂ 5-F F F B-510.CHF₂ 5-CH₃ F F B-511. CHF₂ 5-OCH₃ F F B-512. CHF₂ 6-F F F B-513. CHF₂6-CH₃ F F B-514. CHF₂ 6-OCH₃ F F B-515. CF₃ 3-F F F B-516. CF₃ 3-CH₃ F FB-517. CF₃ 3-OCH₃ F F B-518. CF₃ 5-F F F B-519. CF₃ 5-CH₃ F F B-520. CF₃5-OCH₃ F F B-521. CF₃ 6-F F F B-522. CF₃ 6-CH₃ F F B-523. CF₃ 6-OCH₃ F FB-524. OCH₂F 3-F F F B-525. OCH₂F 3-CH₃ F F B-526. OCH₂F 3-OCH₃ F FB-527. OCH₂F 5-F F F B-528. OCH₂F 5-CH₃ F F B-529. OCH₂F 5-OCH₃ F FB-530. OCH₂F 6-F F F B-531. OCH₂F 6-CH₃ F F B-532. OCH₂F 6-OCH₃ F FB-533. OCHF₂ 3-F F F B-534. OCHF₂ 3-CH₃ F F B-535. OCHF₂ 3-OCH₃ F FB-536. OCHF₂ 5-F F F B-537. OCHF₂ 5-CH₃ F F B-538. OCHF₂ 5-OCH₃ F FB-539. OCHF₂ 6-F F F B-540. OCHF₂ 6-CH₃ F F B-541. OCHF₂ 6-OCH₃ F FB-542. OCF₃ 3-F F F B-543. OCF₃ 3-CH₃ F F B-544. OCF₃ 3-OCH₃ F F B-545.OCF₃ 5-F F F B-546. OCF₃ 5-CH₃ F F B-547. OCF₃ 5-OCH₃ F F B-548. OCF₃6-F F F B-549. OCF₃ 6-CH₃ F F B-550. OCF₃ 6-OCH₃ F F B-551. H H Cl FB-552. F H Cl F B-553. CH₃ H Cl F B-554. OCH₃ H Cl F B-555. CN H Cl FB-556. CH₂F H Cl F B-557. CHF₂ H Cl F B-558. CF₃ H Cl F B-559. OCH₂F HCl F B-560. OCHF₂ H Cl F B-561. OCF₃ H Cl F B-562. H 3-F Cl F B-563. H3-CH₃ Cl F B-564. H 3-OCH₃ Cl F B-565. H 5-F Cl F B-566. H 5-CH₃ Cl FB-567. H 5-OCH₃ Cl F B-568. H 6-F Cl F B-569. H 6-CH₃ Cl F B-570. H6-OCH₃ Cl F B-571. F 3-F Cl F B-572. F 3-CH₃ Cl F B-573. F 3-OCH₃ Cl FB-574. F 5-F Cl F B-575. F 5-CH₃ Cl F B-576. F 5-OCH₃ Cl F B-577. F 6-FCl F B-578. F 6-CH₃ Cl F B-579. F 6-OCH₃ Cl F B-580. CH₃ 3-F Cl F B-581.CH₃ 3-CH₃ Cl F B-582. CH₃ 3-OCH₃ Cl F B-583. CH₃ 5-F Cl F B-584. CH₃5-CH₃ Cl F B-585. CH₃ 5-OCH₃ Cl F B-586. CH₃ 6-F Cl F B-587. CH₃ 6-CH₃Cl F B-588. CH₃ 6-OCH₃ Cl F B-589. OCH₃ 3-F Cl F B-590. OCH₃ 3-CH₃ Cl FB-591. OCH₃ 3-OCH₃ Cl F B-592. OCH₃ 5-F Cl F B-593. OCH₃ 5-CH₃ Cl FB-594. OCH₃ 5-OCH₃ Cl F B-595. OCH₃ 6-F Cl F B-596. OCH₃ 6-CH₃ Cl FB-597. OCH₃ 6-OCH₃ Cl F B-598. CN 3-F Cl F B-599. CN 3-CH₃ Cl F B-600.CN 3-OCH₃ Cl F B-601. CN 5-F Cl F B-602. CN 5-CH₃ Cl F B-603. CN 5-OCH₃Cl F B-604. CN 6-F Cl F B-605. CN 6-CH₃ Cl F B-606. CN 6-OCH₃ Cl FB-607. CH₂F 3-F Cl F B-608. CH₂F 3-CH₃ Cl F B-609. CH₂F 3-OCH₃ Cl FB-610. CH₂F 5-F Cl F B-611. CH₂F 5-CH₃ Cl F B-612. CH₂F 5-OCH₃ Cl FB-613. CH₂F 6-F Cl F B-614. CH₂F 6-CH₃ Cl F B-615. CH₂F 6-OCH₃ Cl FB-616. CHF₂ 3-F Cl F B-617. CHF₂ 3-CH₃ Cl F B-618. CHF₂ 3-OCH₃ Cl FB-619. CHF₂ 5-F Cl F B-620. CHF₂ 5-CH₃ Cl F B-621. CHF₂ 5-OCH₃ Cl FB-622. CHF₂ 6-F Cl F B-623. CHF₂ 6-CH₃ Cl F B-624. CHF₂ 6-OCH₃ Cl FB-625. CF₃ 3-F Cl F B-626. CF₃ 3-CH₃ Cl F B-627. CF₃ 3-OCH₃ Cl F B-628.CF₃ 5-F Cl F B-629. CF₃ 5-CH₃ Cl F B-630. CF₃ 5-OCH₃ Cl F B-631. CF₃ 6-FCl F B-632. CF₃ 6-CH₃ Cl F B-633. CF₃ 6-OCH₃ Cl F B-634. OCH₂F 3-F Cl FB-635. OCH₂F 3-CH₃ Cl F B-636. OCH₂F 3-OCH₃ Cl F B-637. OCH₂F 5-F Cl FB-638. OCH₂F 5-CH₃ Cl F B-639. OCH₂F 5-OCH₃ Cl F B-640. OCH₂F 6-F Cl FB-641. OCH₂F 6-CH₃ Cl F B-642. OCH₂F 6-OCH₃ Cl F B-643. OCHF₂ 3-F Cl FB-644. OCHF₂ 3-CH₃ Cl F B-645. OCHF₂ 3-OCH₃ Cl F B-646. OCHF₂ 5-F Cl FB-647. OCHF₂ 5-CH₃ Cl F B-648. OCHF₂ 5-OCH₃ Cl F B-649. OCHF₂ 6-F Cl FB-650. OCHF₂ 6-CH₃ Cl F B-651. OCHF₂ 6-OCH₃ Cl F B-652. OCF₃ 3-F Cl FB-653. OCF₃ 3-CH₃ Cl F B-654. OCF₃ 3-OCH₃ Cl F B-655. OCF₃ 5-F Cl FB-656. OCF₃ 5-CH₃ Cl F B-657. OCF₃ 5-OCH₃ Cl F B-658. OCF₃ 6-F Cl FB-659. OCF₃ 6-CH₃ Cl F B-660. OCF₃ 6-OCH₃ Cl F

The positions (e.g. 3-/5-/6-) of R³ are relative to the 2- and4-positions of radicals R¹ and R² and to the 1-position of theattachment point of the ring to the SO₂ group.

The preferred compounds among the compounds I.1 to I.128 mentioned aboveare those of the formulae I.1, I.2, I.3, I.4, I.5, I.9, I.13, I.15,I.17, I.19, I.33, I.35, I.49, I.51, I.65, I.67, I.81, I.83, I.97, I.99,I.113 and I.115. More preferred are those of formulae I.1, I.3, I.17,I.19, I.33, I.35, I.49, I.51, I.65, I.67, I.81, I.83, I.97, I.99, I.113and I.115. Particularly preferred are compounds of the formulae I.1 andI.3.

In a specific embodiment, the compounds I are selected from thecompounds specified in the examples, either as a free base or in form ofa pharmaceutically acceptable salt, an N-oxide or a stereoisomer or theracemate or any mixture of stereoisomers thereof.

The compounds I of the invention have a center of chirality in position3 of the 2-oxindole ring. The compounds of the invention may thereforebe in the form of a 1:1 mixture of enantiomers (racemate) or of anonracemic mixture of enantiomers in which one of the two enantiomers,either the enantiomer which rotates the plane of vibration of linearlypolarized light to the left (i e minus rotation) (hereinafter (−)enantiomer) or the enantiomer which rotates the plane of vibration oflinearly polarized light to the right (i.e. plus rotation) (hereinafter(+) enantiomer), is enriched, or of substantially enantiopure compounds,that is to say of substantially enantiopure (−) enantiomer or (+)enantiomer. Since the compounds of the invention have a single center ofasymmetry and no axis/plane of chirality, a nonracemic mixture can alsobe defined as a mixture of enantiomers in which either the R or the Senantiomer predominates. Substantially enantiopure compounds canaccordingly also be defined as substantially enantiopure R enantiomer orsubstantially enantiopure S enantiomer.

“Substantially enantiopure compounds” means in the context of thepresent invention those compounds having an enantiomeric excess (ee; %ee=(R−S)/(R+S)×100 or (S−R)/(S+R)×100) of at least 80% ee, preferably atleast 85% ee, more preferably at least 90% ee, even more preferably atleast 95% ee and in particular at least 98% ee.

In one embodiment of the invention, the compounds of the invention arein the form of substantially enantiopure compounds. Particularlypreferred compounds have an enantiomeric excess of at least 85% ee, morepreferably of at least 90% ee, even more preferably of at least 95% eeand in particular of at least 98% ee.

The invention thus relates both to the pure enantiomers and to mixturesthereof, e.g. mixtures in which one enantiomer is present in enrichedform, but also to the racemates. The invention also relates to thepharmaceutically acceptable salts of the pure enantiomers of compoundsI, and the mixtures of enantiomers in the form of the pharmaceuticallyacceptable salts of compounds I.

Preferred embodiments of the invention are compounds of the formula I asdetailed above which are characterized in that they are in opticallyactive form, and the enantiomer of the relevant compound of the formulaI is the S-enantiomer, in the form of a free base, or a pharmaceuticallyacceptable salt thereof.

Particularly preference is given to compounds of the general formula Iand their pharmaceutically acceptable salts as detailed above in whichthe corresponding S-enantiomer is present in an optical purity(enantiomeric excess, ee) of more than 50% ee, particularly preferablyof at least 80% ee, more preferably of at least 90% ee and even morepreferably of at least 95% ee and in particular of at least 98% ee.

Likewise preferred embodiments of the invention are compounds of thegeneral formula I as detailed above which are characterized in that theyare in optically inactive form, i.e. in the form of the racemate, or inthe form of a pharmaceutically acceptable salt of the racemate.

Examples of synthetic routes for preparing the oxindole derivatives ofthe invention are described below.

The compounds of the invention can be prepared by using methodsdescribed in WO 2005/030755 and WO 2006/005609 for synthesizinganalogous compounds, and the preparation is outlined by way of examplein synthesis schemes 1 to 4. If not indicated otherwise, the variablesin these synthetic schemes have the same meanings as in formula I.

The 3-hydroxy-1,3-dihydroindol-2-ones IV can be obtained by addition ofmetallated benzenes or heterocycles III onto the 3-keto group of theisatins II. The metallated benzenes or heterocycles, such as, forexample, the corresponding Grignard (Mg) or organyllithium compound, canbe obtained in any conventional way from halogen or hydrocarboncompounds. Examples of methods are present in Houben-Weyl, Methoden derOrganischen Chemie, vol. 13, 1-2, chapter on Mg and Li compounds. Theisatins II are either commercially available or were prepared in analogyto methods described in the literature (Advances in HeterocyclicChemistry, A. R. Katritzky and A. J. Boulton, Academic Press, New York,1975, 18, 2-58; J. Brazil. Chem. Soc. 12, 273-324, 2001).

The 3-hydroxyoxindoles IV which comprise an iodine in the 6-memberedaromatic ring, for example in position 5 or 6, i.e. in the position ofthe radicals R¹ or R², can be converted with KCN or Zn(CN)₂ with Pd(0)catalysis in solvents such as dimethylformamide or tetrahydrofuran,where appropriate also with addition of bases such as K₂CO₃ or othercarbonates or amines, at elevated temperature into the analogouscyan-containing 3-hydroxyoxindole IV. Pd(0) salts which can be taken arefor example transition metal complexes which are prepared in situ fromPdCl₂ or PdOAc₂ by addition of phosphines such astris(orthotolyl)phosphine. It is likewise possible to employ commercialpalladium complexes such as, for example, the catalysttetrakis(triphenylphosphine)palladium(0) and/or additions of phosphineligands.

The 3-hydroxyoxindoles IV can be converted into the compounds V whichhave a leaving group LG′ in position 3, where the leaving group LG′ is aconventional leaving group such as, for example, chlorine or bromide.The intermediate V with for example LG′=chlorine can be prepared bytreating the alcohol IV with thionyl chloride in the presence of a basesuch as, for example, pyridine, in a suitable solvent such as, forexample, dichloromethane.

The compounds V can subsequently be reacted with amines, such as, forexample, ammonia, in a substitution reaction to give the amines VI. Thecompounds VI can subsequently be converted by treatment with sulfonylchlorides VII after deprotonation with a strong base such as, forexample, potassium tert-butoxide or sodium hydride in DMF into thesulfonylated product VIII. The sulfonyl chlorides VII employed caneither be purchased or be prepared by known processes (for example J.Med. Chem. 40, 1149 (1997)).

The compounds of the invention of the general formula I which have aurea group in position 3 (in other words: compounds I wherein X¹ is NHand X² is N) can be prepared as described in WO 2005/030755 and WO2006/005609, and shown in synthesis scheme 1, in a two-stage process:firstly, the compounds VIII are reacted with phenyl chloroformate in thepresence of a base such as, for example, pyridine to give thecorresponding phenyl carbamate IX.

Subsequent reaction with amines X, where appropriate at elevatedtemperature and with the addition of auxiliary bases such as, forexample, triethylamine or diisopropylethylamine, leads to the compoundsof the invention of the general formula (I) with a urea bridge (X¹=NH).The amines X can be either purchased or prepared by methods known fromthe literature. Compounds I of the invention with R³=H can be preparedby using appropriate Boc-protected amines (R³=Boc). The Boc protectivegroup can subsequently be removed, for example by treatment withtrifluoroacetic acid in dichloromethane.

Synthesis Scheme 1

The compounds of the invention of the general formula I having acarbamate group in position 3 (in other words: compounds I wherein X¹ isO and X² is N) can be prepared as described in WO 2006/005609 and shownin synthesis scheme 2: firstly, the 3-hydroxy compound IV is reactedwith phenyl chloroformate to give the phenyl carbonate derivatives XIaand/or XIb. The carbamate derivatives XII are obtained with an excess ofamine X and can subsequently be converted under the usual conditions(deprotonation with a strong base such as, for example, sodium hydrideor potassium tert-butoxide in a suitable solvent such as, for example,DMF, followed by treatment with sulfonyl chlorides VII) into thecompounds I of the invention with a carbamate bridge.

Synthesis Scheme 2

The compounds of the invention of the general formula I which have a2-oxo-ethyl group in position 3 (in other words: compounds I wherein X¹is CH₂ and X² is N) can be prepared as shown in synthesis scheme 3.Introduction of the acetic acid group can take place as described in WO2006/005609 in a 4-stage sequence (1. replacement of the leaving groupLG′ in V by the sodium salt of dimethyl malonate, 2. hydrolysis of thefirst ester group, 3. thermal decarboxylation, 4. hydrolysis of thesecond ester group). The amine side chain X can be coupled to thecarboxylic acid XV using standard coupling reagents known in peptidechemistry, such as, for example, EDC(N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride) and HOBT(1-hydroxybenzotriazole) in a solvent such as, for example,N,N-dimethylformamide, or BOP(1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate)in the presence of a base such as triethylamine or diisopropyethylamine.The sulfonylation can take place by deprotonation of the couplingproduct XVI with a strong base such as, for example, sodium hydride orpotassium tert-butoxide, and subsequent treatment with sulfonylchlorides VII in a solvent such as, for example, DMF, and leads to thecompounds I of the invention with an amide bridge.

Synthesis Scheme 3

Compounds I wherein X¹ is NH or O and X² is CH can be prepared as shownin synthesis scheme 4 in a standard amidation or esterification process.Amidation (when X¹ is NH) can be carried out by reacting the amine XVIIwith the acid XVIII under heating and removal of reaction water, but ispreferably carried out by activation of the carboxylic acid XVIII withoxalylchloride [(COCl)₂] or thionylchloride (SOCl₂) to the respectiveacid chloride, followed by reaction with amine XVII. Alternatively,amidation is carried out in the presence of a coupling reagent. Suitablecoupling reagent (activators) are well known and are for instanceselected from carbodiimides, such as DCC (dicyclohexylcarbodiimide) andDIC (diisopropylcarbodiimide), benzotriazole derivatives, such as HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), HBTU((O-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate)and HCTU(1H-benzotriazolium-1-[bis(dimethylamino)methylene]-5-chlorotetrafluoroborate)and phosphonium-derived activators, such as BOP((benzotriazol-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate), Py-BOP((benzotriazol-1-yloxy)-tripyrrolidinphosphonium hexafluorophosphate)and Py-BrOP (bromotripyrrolidinphosphonium hexafluorophosphate).Generally, the activator is used in excess. The benzotriazole andphosphonium coupling reagents are generally used in a basic medium.Alike, esterification (when X¹ is O) can be carried out by reacting thealcohol XVII with the acid XVIII under heating and removal of reactionwater, but is preferably carried out by activation of the carboxylicacid XVIII with oxalylchloride [(COCl)₂] or thionylchloride (SOCl₂) tothe respective acid chloride, followed by reaction with alcohol XVII.

Synthesis Scheme 4

Compounds I wherein X¹ is CH₂ and X² is CH can be prepared in analogy tothe synthetic routes described in Organic and Biomolecular Chemistry2013, 11(40), 6984-6993 starting either from isatin II and the Grignardreagent A-M (III) or starting from the oxindole compounds IV or V andreacting these with either XIX or XX.

In case that XIX is used, Cu(CF₃SO₃)₂ is suitably used as catalyst, andin case that XX is used, Sn(CF₃SO₃)₂ is a suitable catalyst.

Compounds I wherein X¹ is CH₂ and X² is CH can also be prepared inanalogy to the synthetic route described in J. Org. Chem. 2012, 77(24),11325-11332 by decarboxylating β-ketoacid XXI in the presence of anoxindole compound V.

The sequence of reaction steps can be varied. For instance, in schemes 1to 3, the (het)arylsulfonyl group B—SO₂— can be introduced earlier thanshown, e.g. by reacting yet II, IV or V with VII in scheme 1, byreacting yet IV, XIa or XIb with VII in scheme 2 or by reacting yet V,XIII, XIV or XV with VII in scheme 3; or can be introduced later, e.g.after the introduction of X in scheme 1 or by reacting a compound XVII,which does however not carry the B—SO₂— group, with XVIII and only thenwith VII. Spiro compounds X can be used in protected form, if required,e.g. if one of X³, X⁴, X⁵, X⁶ and/or X⁷ is NH and is not substituted bya radical R³, R⁴ or R⁵ which confers protection to this nitrogen ringatom. Suitable protective groups are, for example, C₁-C₄-alkoxycarbonylgroups, such as tert-butoxycarbonyl (Boc), C₁-C₄-alkylcarbonyl groups,such as acetyl, C₁-C₄-alkylsulfonyl, phenylsulfonyl or benzyl. Usually,Boc is used. Moreover, radical R⁵ (if not hydrogen) can be introduced ata later point of time; especially if bound to X⁷. In this case, acompound I′, I″, I′″ or I″″, which does however not carry the radical R⁵and in which X⁷ is NH, is reacted with a suitable precursor compound ofR⁵ (especially if R⁵ is optionally substituted alkyl, alkenyl, alkynylor cycloalkyl), such as R⁵—Y wherein Y is a suitable leaving group suchas Cl, Br, I or the triflate group. Phenyl or heterocyclyl groups R⁵ canbe introduced in a Buchwald-Hartwig reaction using a Pd catalyst.

In analogy to the findings described by Y. Naruse et al. in TetrahedronAsymmetry 2013, 24, 169-171, the above synthetic routes may result inthe formation of two conformers. If the (het)arylsulfonyl group B—SO₂—is introduced in the last step; i.e. after the spiro ring has beenintroduced, mostly only one conformer is obtained.

If not indicated otherwise, the above-described reactions are generallycarried out in a solvent at temperatures between room temperature andthe boiling temperature of the solvent employed. Alternatively, theactivation energy which is required for the reaction can be introducedinto the reaction mixture using microwaves, something which has provedto be of value, in particular, in the case of the reactions catalyzed bytransition metals (with regard to reactions using microwaves, seeTetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a generalmanner, “Microwaves in Organic Synthesis”, André Loupy (Ed.), Wiley-VCH2002.

The acid addition salts of compounds I are prepared in a customarymanner by mixing the free base with a corresponding acid, whereappropriate in solution in an organic solvent, for example a loweralcohol, such as methanol, ethanol or propanol, an ether, such as methyltert-butyl ether or diisopropyl ether, a ketone, such as acetone ormethyl ethyl ketone, or an ester, such as ethyl acetate.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the preparation methods are within routinetechniques.

Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protective Groups in OrganicSynthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporatedherein by reference in its entirety. Synthesis of the compounds of theinvention may be accomplished by methods analogous to those described inthe synthetic scheme described hereinabove and in specific examples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic exampiessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

The present invention moreover relates to compounds of formula I asdefined above, wherein at least one of the atoms has been replaced byits stable, non-radioactive isotope (e.g., hydrogen by deuterium, ¹²C by¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) and preferably wherein at least onehydrogen atom has been replaced by a deuterium atom.

Of course, the unlabeled compounds according to the invention mightnaturally include certain amounts of these respective isotopes.Therefore, when referring to compounds I, wherein at least one of theatoms has been replaced by its stable, non-radioactive isotope, it willbe understood that the isotope is present in a higher amount than wouldnaturally occur.

Stable isotopes (e.g., deuterium, ¹³C, ¹⁵N, ¹⁸O) are nonradioactiveisotopes which contain one additional neutron than the normally abundantisotope of the respective atom. Deuterated compounds have been used inpharmaceutical research to investigate the in vivo metabolic fate of thecompounds by evaluation of the mechanism of action and metabolic pathwayof the non deuterated parent compound (Blake et al. J. Pharm. Sci. 64,3, 367-391 (1975)). Such metabolic studies are important in the designof safe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp. 2-36, Academic press,London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).

Incorporation of a heavy atom, particularly substitution of deuteriumfor hydrogen, can give rise to an isotope effect that could alter thepharmacokinetics of the drug.

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These changes may influencethe fate of the drug at different steps along its passage through thebody. Absorption, distribution, metabolism or excretion can be changed.Absorption and distribution are processes that depend primarily on themolecular size and the lipophilicity of the substance. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction.

Drug metabolism can give rise to large isotopic effect if the breakingof a chemical bond to a deuterium atom is the rate limiting step in theprocess. While some of the physical properties of a stableisotope-labeled molecule are different from those of the unlabeled one,the chemical and biological properties are the same, with one importantexception: because of the increased mass of the heavy isotope, any bondinvolving the heavy isotope and another atom will be stronger than thesame bond between the light isotope and that atom. In any reaction inwhich the breaking of this bond is the rate limiting step, the reactionwill proceed slower for the molecule with the heavy isotope due to“kinetic isotope effect”. A reaction involving breaking a C-D bond canbe up to 700 percent slower than a similar reaction involving breaking aC—H bond. If the C-D bond is not involved in any of the steps leading tothe metabolite, there may not be any effect to alter the behavior of thedrug. If a deuterium is placed at a site involved in the metabolism of adrug, an isotope effect will be observed only if breaking of the C-Dbond is the rate limiting step. There is evidence to suggest thatwhenever cleavage of an aliphatic C—H bond occurs, usually by oxidationcatalyzed by a mixed-function oxidase, replacement of the hydrogen bydeuterium will lead to observable isotope effect. It is also importantto understand that the incorporation of deuterium at the site ofmetabolism slows its rate to the point where another metabolite producedby attack at a carbon atom not substituted by deuterium becomes themajor pathway a process called “metabolic switching”.

Deuterium tracers, such as deuterium-labeled drugs and doses, in somecases repeatedly, of thousands of milligrams of deuterated water, arealso used in healthy humans of all ages, including neonates and pregnantwomen, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control.Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al.Am. J. Obstet Gynecol. 1981 139: 948). Thus, it is clear that anydeuterium released, for instance, during the metabolism of compounds ofthis invention poses no health risk.

The weight percentage of hydrogen in a mammal (approximately 9%) andnatural abundance of deuterium (approximately 0.015%) indicates that a70 kg human normally contains nearly a gram of deuterium. Furthermore,replacement of up to about 15% of normal hydrogen with deuterium hasbeen effected and maintained for a period of days to weeks in mammals,including rodents and dogs, with minimal observed adverse effects(Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson JF, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J.Physiol. 1961 201: 357). Higher deuterium concentrations, usually inexcess of 20%, can be toxic in animals. However, acute replacement of ashigh as 15%-23% of the hydrogen in humans' fluids with deuterium wasfound not to cause toxicity (Blagojevic N et al. in “Dosimetry &Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares Gand Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23: 251 (1997)).

Increasing the amount of deuterium present in a compound above itsnatural abundance is called enrichment or deuterium-enrichment. Examplesof the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71,75, 79, 84, 88, 92, 96, to about 100 mol %.

The hydrogens present on a particular organic compound have differentcapacities for exchange with deuterium. Certain hydrogen atoms areeasily exchangeable under physiological conditions and, if replaced bydeuterium atoms, it is expected that they will readily exchange forprotons after administration to a patient. Certain hydrogen atoms may beexchanged for deuterium atoms by the action of a deuteric acid such asD2SO4/D2O. Alternatively, deuterium atoms may be incorporated in variouscombinations during the synthesis of compounds of the invention. Certainhydrogen atoms are not easily exchangeable for deuterium atoms. However,deuterium atoms at the remaining positions may be incorporated by theuse of deuterated starting materials or intermediates during theconstruction of compounds of the invention.

Deuterated and deuterium-enriched compounds of the invention can beprepared by using known methods described in the literature. Suchmethods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure. Relevant procedures and intermediates are disclosed,for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996);Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B etal., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223,WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and USPatent Application Publication Nos. 20090137457; 20090131485;20090131363; 20090118238; 20090111840; 20090105338; 20090105307;20090105147; 20090093422; 20090088416; 20090082471, the methods arehereby incorporated by reference.

A further aspect of the present invention relates to a pharmaceuticalcomposition comprising at least one compound of the general formula Iand/or an N-oxide, a stereoisomer or a pharmaceutically acceptable saltthereof as detailed above, and a pharmaceutically acceptable carrier; orcomprising at least one compound I wherein at least one of the atoms hasbeen replaced by its stable, non-radioactive isotope, preferably whereinat least one hydrogen atom has been replaced by a deuterium atom, incombination with at least one pharmaceutically acceptable carrier and/orauxiliary substance. Suitable carriers depend inter alia on the dosageform of the composition and are known in principle to the skilledworker. Some suitable carriers are described hereinafter.

The present invention furthermore relates to a compound I as definedabove or an N-oxide, a stereoisomer or a pharmaceutically acceptablesalt thereof for use as a medicament. The present invention also relatesto a compound I as defined above or an N-oxide, a stereoisomer or apharmaceutically acceptable salt thereof for the treatment ofvasopressin-related diseases, especially of disorders which respond tothe modulation of the vasopressin receptor and in particular of the V1breceptor.

A further aspect of the present invention relates to the use ofcompounds of the formula I and/or of an N-oxide, a stereoisomer or ofpharmaceutically acceptable salts thereof for the manufacture of amedicament for the treatment and/or prophylaxis of vasopressin-relateddiseases, especially of disorders which respond to the modulation of thevasopressin receptor and in particular of the V1b receptor.

Vasopressin-related diseases are those in which the progress of thedisease is at least partly dependent on vasopressin, i.e. diseases whichshow an elevated vasopressin level which may contribute directly orindirectly to the pathological condition. In other words,vasopressin-related diseases are those which can be influenced bymodulating the vasopressin receptor, for example by administration of avasopressin receptor ligand (agonist, antagonist, partialantagonist/agonist, inverse agonist etc.).

Affective disorders have been related to excessive vasopressin function.Therefore, treatment with compounds targeting the vasopressin system,such as vasopressin antagonists are likely to benefit patients sufferingfrom affective disorders (see for example Surget A., Belzung C.,Involvement of vasopressin in affective disorders, Eur. J. Pharm. 2008,583, 340-349). Affective disorders (mood disorders) include depressivedisorders, anxiety disorders, obsessive-compulsive and relateddisorders, trauma and stressor-related disorders as well as bipolar andrelated disorders. V1b antagonist have been shown to have anti-drugabuse effects and reduce drug withdrawal effect (see e.g. Zhou Y., LeriF., Cummins E., Hoeschele M., Kreek M. J., Involvement of argininevasopressin and V1b receptor in heroin withdrawal and heroin seekingprecipitated by stress and by heroin. Neuropsychopharmacology, 2008, 33,226-236). Therefore, compounds targeting the vasopressin system, such asvasopressin antagonists, are thought to be effective for treatment ofsubstance-related and addictive disorders. V1b receptors play a role ina range of emotional responses such as aggression. Attenuating V1breceptor function genetically or with antagonist reduces aggressivebehavior (Blanchard R. J., Griebel G., Farrokhi C., Markham C., Yang M.,Blanchard D. C., AVP V1b selective antagonist SSR149415 blocksaggressive behaviors in hamsters. Pharmacol. Biochem. Behay. 2005, 80,189-194; Wersinger S. R., Ginns E. I., O'Carroll A. M., Lolait S. J.,Young W. S., III, Vasopressin V1b receptor knockout reduces aggressivebehavior in male mice. Mol. Psychiatry, 2002, 7, 975-984). Therefore,attenuating V1b antagonists functioning is likely to reduce aggressionand agitation in disorders such as Alzheimer's disease and schizophreniaand other psychiatric and neurological disorders in which aggressivebehavior occurs, such as Alzheimer's disease, schizophrenia, bipolardisorder, frontal lobe injuries or substance use disorders.

High cortisol levels have been correlated to reduced cognitiveperformance in elderly and AD (Alzheimer's disease) patients, and suchcorrelations are more pronounced in subjects carrying the APOε4 allele,which is a risk factor for AD (see for example Lee B. K., Glass T. A.,Wand G. S., McAtee M. J., Bandeen-Roche K., Bolla K. I., Schwartz B. S.,Apolipoprotein e genotype, cortisol, and cognitive function incommunity-dwelling older adults. Am. J. Psychiatry 2008, 165,1456-1464). Furthermore, increased plasma cortisol has been associatedwith more rapid disease progression in AD patients. Animal studies showan interaction between glucocorticoids and AD pathology, includingamyloid precursor protein and tau accumulation (see for example BudasG., Coughlan C. M., Seckl J. R., Breen K. C., The effect ofcorticosteroids on amyloid beta precursor protein/amyloid precursor-likeprotein expression and processing in vivo. Neurosci. Lett., 1999, 276,61-64). Cognitive performance can be impaired by stress or exposure tohigh doses of corticosterone in laboratory animals (for review seeRoozendaal B., Systems mediating acute glucocorticoid effects on memoryconsolidation and retrieval. Prog. Neuropsychopharmacol. Biol.Psychiatry, 2003, 27, 1213-1223). Therefore, lowering cortisol bytreatment with V1b antagonist may enhance cognition or prevent/slow downthe pathology or cognitive decline Alzheimer's disease patients and inpatients with other cognitive impairment such as schizophrenia anddepression.

In a preferred embodiment, the present invention relates to the use ofcompounds of the invention of the formula I or of an N-oxide, astereoisomer or of pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofdiseases selected from diabetes, insulin resistance, nocturnal enuresis,incontinence and diseases in which impairments of blood clotting occur,and/or for delaying micturition; as well as to compounds of theinvention of the formula I or of an N-oxide, a stereoisomer or ofpharmaceutically acceptable salts thereof for the treatment and/orprophylaxis of the above-listed diseases. The term “diabetes” means alltypes of diabetes, especially diabetes mellitus (including type I andespecially type II), diabetes renalis and in particular diabetesinsipidus. The types of diabetes are preferably diabetes mellitus oftype II (with insulin resistance) or diabetes insipidus.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or of pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofdiseases selected from hypertension, pulmonary hypertension, heartfailure, myocardial infarction, coronary spasm, unstable angina, PTCA(percutaneous transluminal coronary angioplasty), ischemias of theheart, impairments of the renal system, edemas, renal vasospasm,necrosis of the renal cortex, hyponatremia, hypokalemia,Schwartz-Bartter syndrome, impairments of the gastrointestinal tract,gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcers,emesis, emesis occurring during chemotherapy, and travel sickness; aswell as to compounds of the invention of the formula I or of an N-oxide,a stereoisomer or of pharmaceutically acceptable salts thereof for thetreatment and/or prophylaxis of the above-listed diseases.

The compounds of the invention of the formula I or their N-oxides,stereoisomers or pharmaceutically acceptable salts or the pharmaceuticalcomposition of the invention can also be used for the treatment ofvarious vasopressin-related complaints which have central nervous causesor alterations in the HPA axis (hypothalamic pituitary adrenal axis),for example for affective disorders such as depressive disorders,anxiety disorders, obsessive-compulsive and related disorders, traumaand stressor-related disorders, and bipolar and related disorders.Depressive disorders include for example dysthymic disorders, majordepression, seasonal depression, treatment-resistant depressiondisorders, disruptive mood dysregulation disorder, premenstrualdysphoric disorder, substance/medication-induced depressive disorder,depressive disorder due to another medical condition, or childhood onsetmood disorders. Anxiety disorders include for example phobias, specificphobias, general anxiety disorders, panic disorders, drugwithdrawal-induced anxiety disorders, separation anxiety disorder,selective mutism, social anxiety disorder, agoraphobia,substance/medication-induced anxiety disorder and anxiety disorder dueto another medical condition. Obsessive-compulsive and related disordersinclude for example obsessive-compulsive disorder, body dysmorphicdisorder, hoarding disorder, trichotillomania, excoriation disorder,substance/medication-induced obsessive-compulsive and related disorderand other specified obsessive-compulsive and related disorders. Traumaand stressor-related disorders include for example reactive attachmentdisorder, disinhibited social engagement disorder, post-traumatic stressdisorder, acute stress disorder, adjustment disorder and other specifiedtrauma- and stressor-related disorders. Bipolar and related disordersinclude for example bipolar I disorder, bipolar II disorder, cyclothymicdisorder, substance/medication-induced bipolar and related disorder,bipolar and related disorder due to another medical condition andunspecified bipolar and related disorder.

Vasopressin-related complaints which have central nervous causes oralterations in the HPA axis are further cognitive disorders such asAlzheimer's disease, MCI (Mild Cognitive Impairment) and CIAS (CognitiveImpairment Associated with Schizophrenia).

The compounds of the invention of the formula I and their N-oxides, astereoisomers or pharmaceutically acceptable salts or the pharmaceuticalcomposition of the invention can likewise be employed for the treatmentof anxiety disorders and stress-dependent anxiety disorders, such as,for example, generalized anxiety disorders, phobias, specific phobias,post-traumatic anxiety disorders, panic anxiety disorders,obsessive-compulsive anxiety disorders, acute stress-dependent anxietydisorders, drug withdrawal-induced anxiety disorders, separation anxietydisorder, selective mutism, social anxiety disorder, agoraphobia,substance/medication-induced anxiety disorder and anxiety disorder dueto another medical condition and social phobia. The compounds of theinvention of the formula I and their N-oxides, a stereoisomers orpharmaceutically acceptable salts or the pharmaceutical composition ofthe invention can likewise be employed for the treatment ofobsessive-compulsive and related disorders, including, for example,obsessive-compulsive disorder, body dysmorphic disorder, hoardingdisorder, trichotillomania, excoriation disorder,substance/medication-induced obsessive-compulsive and related disorderand other specified obsessive-compulsive and related disorders. Thecompounds of the invention of the formula I and their N-oxides, astereoisomers or pharmaceutically acceptable salts or the pharmaceuticalcomposition of the invention can likewise be employed for the treatmentof trauma and stressor-related disorders, including, for example,reactive attachment disorder, disinhibited social engagement disorder,post-traumatic stress disorder, acute stress disorder, adjustmentdisorder and other specified trauma- and stressor-related disorders.

The compounds of the invention of the formula I and their N-oxides,stereoisomers or pharmaceutically acceptable salts or the pharmaceuticalcomposition of the invention can likewise be employed for the treatmentand/or prophylaxis of social impairment, such as autism or socialimpairment related with schizophrenia.

The compounds of the invention of the formula I and their N-oxides,stereoisomers or pharmaceutically acceptable salts or the pharmaceuticalcomposition of the invention can likewise be employed for the treatmentand/or prophylaxis of increased aggression in conditions selected fromAlzheimer's disease, schizophrenia, bipolar disorder, frontal lobeinjuries and substance use disorders.

The compounds of the invention can furthermore also be employed for thetreatment of memory impairments, Alzheimer's disease, psychoses,psychotic disorders, sleep disorders and/or Cushing's syndrome, and allstress-dependent diseases.

Accordingly, a further preferred embodiment of the present inventionrelates to the use of compounds of the invention of the formula I or ofan N-oxide, a stereoisomer or pharmaceutically acceptable salts thereoffor the manufacture of a medicament for the treatment of affectivedisorders; as well as to compounds of the invention of the formula I orof an N-oxide, a stereoisomer or of pharmaceutically acceptable saltsthereof for the treatment of affective disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of anxiety disordersand/or stress-dependent anxiety disorders; as well as to compounds ofthe invention of the formula I or of an N-oxide, a stereoisomer or ofpharmaceutically acceptable salts thereof for the treatment of theabove-listed disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of memory impairmentsand/or Alzheimer's disease; as well as to compounds of the invention ofthe formula I or of an N-oxide, a stereoisomer or of pharmaceuticallyacceptable salts thereof for the treatment of the above-listed diseases.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of psychoses and/orpsychotic disorders; as well as to compounds of the invention of theformula I or of an N-oxide, a stereoisomer or of pharmaceuticallyacceptable salts thereof for the treatment of the above-listeddisorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of Cushing's syndrome orother stress-dependent diseases; as well as to compounds of theinvention of the formula I or of an N-oxide, a stereoisomer or ofpharmaceutically acceptable salts thereof for the treatment of theabove-listed diseases.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of sleep disorders; aswell as to compounds of the invention of the formula I or of an N-oxide,a stereoisomer or of pharmaceutically acceptable salts thereof for thetreatment of sleep disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of depressive disorders;as well as to compounds of the invention of the formula I or of anN-oxide, a stereoisomer or of pharmaceutically acceptable salts thereoffor the treatment and/or prophylaxis of depressive disorders. In thecase of depressive disorders, specific mention is to be made ofchildhood onset mood disorders, i.e. depressive moods having their onsetin childhood, but also of major depression, seasonal depression, bipolarand related disorders, dysthymic disorders, disruptive mooddysregulation disorder, premenstrual dysphoric disorder,substance/medication-induced depressive disorder, and depressivedisorder due to another medical condition, and especially of majordepression and seasonal depression as well as of the depressive phasesof bipolar disorders. Bipolar and related disorders include for examplebipolar I disorder, bipolar II disorder, cyclothymic disorder,substance/medication-induced bipolar and related disorder, bipolar andrelated disorder due to another medical condition and unspecifiedbipolar and related disorder. The invention also relates to compounds ofthe formula I or N-oxides, stereoisomers or pharmaceutically acceptablesalts thereof for the manufacture of a medicament for the treatment oftreatment-resistant depression disorders and for the use in an add-ontherapy of depressive disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment of vasomotor symptomsand/or thermoregulatory dysfunctions such as, for example, the hot flushsymptom; as well as to compounds of the invention of the formula I or ofan N-oxide, a stereoisomer or of pharmaceutically acceptable saltsthereof for the treatment of the above-listed diseases.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment and/or prophylaxis of drugor pharmaceutical dependencies and/or dependencies mediated by otherfactors, for the treatment of drug-use disorders, for the treatmentand/or prophylaxis of stress caused by withdrawal of one or more factorsmediating the dependence and/or for the treatment and/or prophylaxis ofstress-induced relapses into drug or pharmaceutical dependencies and/ordependencies mediated by other factors; as well as to compounds of theinvention of the formula I or of an N-oxide, a stereoisomer or ofpharmaceutically acceptable salts thereof for the treatment and/orprophylaxis of the above-listed diseases. To be more precise, thepresent invention relates to the use of compounds of the invention ofthe formula I or of an N-oxide, a stereoisomer or pharmaceuticallyacceptable salts thereof for the manufacture of a medicament for thetreatment and/or prophylaxis of substance-related and addictivedisorders such as substance use disorder, substance-induced disorder,alcohol use disorder, alcohol intoxication, alcohol withdrawal,unspecified alcohol-related disorder, caffeine intoxication, caffeinewithdrawal, unspecified caffeine disorder, cannabis use disorder,cannabis withdrawal, unspecified cannabis-related disorder,phencyclidine use disorder, other hallucinogen use disorders,phencyclidine intoxication, other hallucinogen disorders, hallucinogenpersisting perception disorder, unspecified phencyclidine disorder,inhalant use disorder, inhalant intoxication, opioid use disorder,opioid withdrawal, sedative, hypnotic or anxiolytic use disorder,sedative, hypnotic or anxiolytic withdrawal, stimulant use disorder,stimulant intoxication, stimulant withdrawal, tobacco use disorder,tobacco withdrawal, unspecified tobacco-related disorder, other (orunknown) substance use disorders, other (or unknown) substanceintoxication, other (or unknown) substance withdrawal, other (orunknown) substance related disorder and gambling disorder; as well as tocompounds of the invention of the formula I or of an N-oxide, astereoisomer or of pharmaceutically acceptable salts thereof for thetreatment and/or prophylaxis of the above-listed diseases.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofschizophrenia and/or psychosis; as well as to compounds of the inventionof the formula I or of an N-oxide, a stereoisomer or of pharmaceuticallyacceptable salts thereof for the treatment and/or prophylaxis of theabove-listed disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or of an N-oxide, astereoisomer or pharmaceutically acceptable salts thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofpain, e.g. acute or chronic pain, preferably chronic pain, especiallyneuropathic pain; as well as to compounds of the invention of theformula I or of an N-oxide, a stereoisomer or of pharmaceuticallyacceptable salts thereof for the treatment and/or prophylaxis of theabove-listed disorders. Chronic pain may be a complex regional painsyndrome, pain arising from peripheral neuropathies, post-operativepain, chronic fatigue syndrome pain, tension-type headache, pain arisingfrom mechanical nerve injury and severe pain associated with diseasessuch as cancer, metabolic disease, neurotropic viral disease,neurotoxicity, inflammation, multiple sclerosis or any pain arising as aconsequence of or associated with stress or depressive illness.

A further aspect of the invention relates to a compound I orpharmaceutically acceptable salts thereof for use as a medicament, andto a compound I or an N-oxide, a stereoisomer or pharmaceuticallyacceptable salts thereof for the manufacture of a medicament for thetreatment and/or prophylaxis of the above-defined diseases.

A further aspect of the invention relates to a method for the treatmentand/or prophylaxis of vasopressin-related diseases, in which aneffective amount of at least one compound of the invention of theformula I or of an N-oxide, a stereoisomer or of at least onepharmaceutically acceptable salt thereof or of a pharmaceuticalcomposition of the invention is administered to a patient in needthereof.

Concerning the definition of vasopressin-related diseases, reference ismade to the above statements made in context with the use according tothe invention. Thus, preferred embodiments of the method of theinvention correspond to preferred embodiments of the use according tothe invention.

The patient to be treated prophylactically or therapeutically with themethod of the invention is preferably a mammal, for example a human or anonhuman mammal or a nonhuman transgenic mammal Specifically it is ahuman.

The compounds of the general formula I and their pharmaceuticallyacceptable salts as detailed above can be prepared by a skilled workerwith knowledge of the technical teaching of the invention inimplementing and/or in analogous implementation of process steps knownper se.

The compounds I and/or their pharmaceutically acceptable salts, N-oxidesand their stereoisomers are distinguished by having a selectivity forthe vasopressin V1b receptor subtype vis-à-vis at least one of theclosely related vasopressin/oxytocin receptor subtypes (for examplevasopressin V1a, vasopressin V2 and/or oxytocin).

Alternatively, or preferably in addition, the compounds I and/or theirpharmaceutically acceptable salts, N-oxides and a stereoisomers aredistinguished by having an improved metabolic stability.

The metabolic stability of a compound can be measured for example byincubating a solution of this compound with liver microsomes fromparticular species (for example rat, dog or human) and determining thehalf-life of the compound under these conditions (R S Obach, Curr OpinDrug Discov Devel. 2001, 4, 36-44). It is possible in this connection toconclude from an observed longer half-life that the metabolic stabilityof the compound is improved. The stability in the presence of humanliver microsomes is of particular interest because it makes it possibleto predict the metabolic degradation of the compound in the human liver.Compounds with increased metabolic stability (measured in the livermicrosome test) are therefore probably also degraded more slowly in theliver. The slower metabolic degradation in the liver may lead to higherand/or longer-lasting concentrations (active levels) of the compound inthe body, so that the elimination half-life of the compounds of theinvention is increased. Increased and/or longer-lasting active levelsmay lead to a better activity of the compound in the treatment orprophylaxis of various vasopressin-related diseases. In addition, animproved metabolic stability may lead to an increased bioavailabilityafter oral administration, because the compound is subject, afterabsorption in the intestine, to less metabolic degradation in the liver(so-called first pass effect). An increased oral bioavailability may,owing to an increased concentration (active level) of the compound, leadto a better activity of the compound after oral administration.

The compounds of the invention are effective after administration byvarious routes. Possible examples are intravenous, intramuscular,subcutaneous, topical, intratracheal, intranasal, transdermal, vaginal,rectal, sublingual, buccal or oral administration, and administration isfrequently intravenous, intramuscular or, in particular, oral.

The present invention also relates to pharmaceutical compositions whichcomprise an effective dose of a compound I of the invention and/or anN-oxide, a stereoisomer and/or a pharmaceutically acceptable saltthereof and suitable pharmaceutical carriers (drug carriers).

These drug carriers are chosen according to the pharmaceutical form andthe desired mode of administration and are known in principle to theskilled worker.

The compounds of the invention of the formula I, their N-oxides,stereoisomers or optionally suitable salts of these compounds can beused to produce pharmaceutical compositions for oral, sublingual,buccal, subcutaneous, intramuscular, intravenous, topical,intratracheal, intranasal, transdermal, vaginal or rectaladministration, and be administered to animals or humans in uniformadministration forms, mixed with conventional pharmaceutical carriers,for the prophylaxis or treatment of the above disorders or diseases.

The suitable administration forms (dose units) include forms for oraladministration such as tablets, gelatin capsules, powders, granules andsolutions or suspensions for oral intake, forms for sublingual, buccal,intratracheal or intranasal administration, aerosols, implants, forms ofsubcutaneous, intramuscular or intravenous administration and forms ofrectal administration.

The compounds of the invention can be used in creams, ointments orlotions for topical administration.

In order to achieve the desired prophylactic or therapeutic effect, thedose of the active ingredient can vary between 0.01 and 50 mg per kg ofbody weight and per day.

Each unit dose may comprise from 0.05 to 5000 mg, preferably 1 to 1000mg, of the active ingredient in combination with a pharmaceuticalcarrier. This unit dose can be administered once to 5 times a day, sothat a daily dose of from 0.5 to 25 000 mg, preferably 1 to 5000 mg, isadministered.

If a solid composition is prepared in the form of tablets, the activeingredient is mixed with a solid pharmaceutical carrier such as gelatin,starch, lactose, magnesium stearate, talc, silicon dioxide or the like.

The tablets can be coated with sucrose, a cellulose derivative oranother suitable substance or be treated otherwise in order to display asustained or delayed activity and to release a predetermined amount ofthe active ingredient continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with an extender and including the resulting mixturein soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops may contain active ingredients together with asweetener, which is preferably calorie-free, methylparaben orpropylparaben as antiseptics, a flavoring and a suitable coloringsubstance.

Water-dispersible powders or granules may comprise the activeingredients mixed with dispersants, wetting agents or suspending agents,such as polyvinylpyrrolidones, and sweeteners or masking flavors.

Rectal or vaginal administration is achieved by using suppositorieswhich are prepared with binders which melt at rectal temperature, forexample cocoa butter or polyethylene glycols. Parenteral administrationis effected by using aqueous suspensions, isotonic saline solutions orsterile and injectable solutions which comprise pharmacologicallyacceptable dispersants and/or wetting agents, for example propyleneglycol or polyethylene glycol.

The active ingredient may also be formulated as microcapsules orcentrosomes, if suitable with one or more carriers or additives.

The compositions of the invention may, in addition to the compounds ofthe invention, comprise other active ingredients which may be beneficialfor the treatment of the disorders or diseases indicated above.

The present invention thus further relates to pharmaceuticalcompositions in which a plurality of active ingredients are presenttogether, where at least one of these is a compound I of the invention,or salt thereof.

The invention is explained in more detail below by means of examples,but the examples are not to be understood to be restrictive.

The compounds of the invention can be prepared by various syntheticroutes. The methods mentioned, as described accordingly in synthesisschemes 1 to 4, are explained in greater detail merely by way of exampleusing the given examples without being exclusively restricted tosynthesis routes 1 to 4 or analogous methods.

EXPERIMENTAL SECTION

Abbreviations used:

-   rt room temperature (20-25° C.)-   h hour(s)-   min minute(s)-   d day(s)-   quant. quantitative-   eq. equivalents)-   conc. concentrated-   TLC thin layer chromatography-   RP reversed phase-   aq. aqueous-   MeOH methanol-   EtOH ethanol-   THF: tetrahydrofuran-   DMF dimethylformamide-   DMSO: dimethyl sulfoxide-   EtOAc ethyl acetate-   TFA: trifluoroacetic acid-   DIPEA diisopropylethyl amine-   p: pseudo (for example pt pseudo triplet)-   b: broad (for example bs broad singlet)-   s: singlet-   d: doublet-   t: triplet-   m: multiplet-   dd: doublet of doublets-   dt: doublet of triplets-   tt: triplet of triplets    I. Preparation of Compounds of Formula I

Example 1N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) and R^(8c) are H and R^(8b)is methoxy)

1.1 (S)-Phenyl(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamate

The title compound was prepared as described in WO2009/071691.

ESI-MS: [M+K⁺]=623.2; [M+Na⁺]=608.2; [M+H⁺]=585.2

1.2 (S)-tert-Butyl6-((5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

DIPEA (2.05 mmol, 0.36 ml) was added to a suspension of tert-butyl2,6-diazaspiro[3.3]-heptane-2-carboxylate oxalate (0.41 mmol, 118 mg) inCH₂Cl₂ (10 ml). Once in solution, (S)-phenyl(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamate(0.41 mmol, 240 mg) was added and the mixture was stirred for 12 h. Themixture was poured into cold 5% aq. K₂CO₃ (10 ml) and extracted withCH₂Cl₂ (3×10 ml); and the organic phases were combined, washed withwater (3×10 ml), dried on Na₂SO₄, filtered, evaporated, and finallypassed through a silicagel column (eluent: EtOAc). Yield: 205.5 mg(73%).

ESI-MS: [M⁺−55 (isobutene)]=633.2; [M+H⁺]=689.2

1.3(S)-N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide

TFA (20 eq., 5.95 mmol, 0.46 ml) was added to a solution of(S)-tert-butyl6-((5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(0.30 mmol, 205 mg) in CH₂Cl₂ (10 ml). The mixture was stirred at rt for1 h, poured into cold 5% aq. K₂CO₃ (10 ml) and extracted with CH₂Cl₂(3×10 ml). The organic phases were combined, washed with water (3×10ml), dried on Na₂SO₄, filtered, evaporated and finally passed through asilicagel column (eluent: CH₂Cl₂:2M NH₃/EtOH 17:3). Yield: 52.7 mg(30%).

ESI-MS: [M+H⁺]=589.3

1.4N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S)-N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxo-indolin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide(0.04 mmol, 25 mg), 2-morpholinoacetaldehyde (NaHSO₃-salt, 0.04 mmol, 10mg), sodium acetate (0.09 mmol, 7 mg) and acetic acid (conc., 0.09 mmol,5 mg) were dissolved in EtOH (1.5 ml) and stirred for 1 h. NaCNBH₃ (0.05mmol, 3.2 mg) was added portionwise and stirred at rt for 12 h. Themixture was poured into cold 5% aq. K₂CO₃ (5 ml) and extracted withethyl acetate (3×5 ml); the organic phases were combined, washed withwater (3×5 ml) and dried on Na₂SO₄, filtered, evaporated and finallypassed through a silicagel column (eluent: CH₂Cl₂:2M NH₃/EtOH 19:1).Solvents were evaporated, the residue precipitated in water and thefiltrate evaporated in vacuo. Yield: 4.81 mg (16%).

ESI-MS: [M+H⁺]=702.3

The product was obtained in form of two conformers. These conformerswere separated via RP-HPLC with following column: LUNA C18 Axia 100A 5μ75×30; flow 40 ml/min; eluent gradient H₂O/10-90% methanol+0.1%trifluoroacetic acid.

Conformer 1A ofN-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)-sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;2,2,2-trifluoroacetic acid

ESI-MS: [M+H⁺]=702.2

¹H NMR (CDCl₃, 600 MHz): d=8.22 (d, 1H), 7.85-7.78 (m, 2H), 7.78-7.72(m, 2H), 7.37 (s br, 1H), 7.00 (s br, 1H), 6.94-6.85 (m br, 4H incl.6.89 d), 4.41 (m sym., 2H), 4.35-4.30 (m, 2H), 4.30-4.22 (m, 3H),4.17-4.03 (m br, 2H), 3.94-3.84 (m, 7H incl 3.87 s), 3.71 (br. s., 1H),3.54-3.45 (m, 2H incl. 3.50 s), 3.16 (s br., 2H), 3.04 (br. s., 4H),1.23 (m sym., 4H)

Conformer 1B ofN-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;2,2,2-trifluoroacetic acid

ESI-MS: [M+H⁺]=702.2

¹H NMR (CDCl₃, 600 MHz): d=8.13 (d, 1H), 8.05 (d, 2H), 8.00 (d, 1H),7.64 (s, 1H), 7.61 (d, 1H), 6.99 (d, 2H), 6.85 (m sym., 1H), 6.44 (s,1H), 4.52 (m sym., 2H), 4.26 (dd, 4H), 4.06 (s br., 4H), 3.94 (m, 4H),3.88 (s, 3H), 3.59 (m sym., 2H), 3.24 (m sym., 2H), 3.10 (br. s., 4H),1.46 (t, 3H).

The following compounds were prepared analogously:

Example 2N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(3-morpholinopropyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 3-(morpholin-4-yl)-n-propyl, R^(8a) and R^(8c) are H andR^(8b) is methoxy)

ESI-MS: [M+H⁺]=716.3

The product was obtained in form of two conformers. These conformerswere identified via HPLC (Column: Zorbax Extended C18, 50×2.1 mm ID,1.8μ, System: Acetonitrile/Formic acid, Flow: 0.7 ml/min, Inj. Vol: 1 μlTemp: 65° C.):

-   Conformer 2A: retention time: 1.38 min-   Conformer 2B: retention time: 1.46 min

Example 3N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is methoxy, R^(8b) is F andR^(8c) is H)

ESI-MS: [M+H⁺]=720.3

The product was obtained in form of two conformers. These conformerswere identified via HPLC (Column: Zorbax Extended C18, 50×2.1 mm ID,1.8μ, System: Acetonitrile/Formic acid, Flow: 0.7 ml/min, Inj. Vol: 1 μlTemp: 65° C.):

-   Conformer 3A: retention time: 1.52 min-   Conformer 3B: retention time: 1.61 min

Example 4N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.65, wherein X¹ is NH, R¹ is CN,R² is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8b) is methoxy and R^(8c) isH)

ESI-MS: [M+H⁺]=703.3

The product was obtained in form of two conformers. These conformerswere identified via HPLC (Column: Zorbax Extended C18, 50×2.1 mm ID,1.8μ, System: Acetonitrile/Formic acid, Flow: 0.7 ml/min, Inj. Vol: 1 μlTemp: 65° C.):

-   Conformer 4A: retention time: 1.48 min-   Conformer 4B: retention time: 1.55 min

Example 5N-[(3S)-5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is H, R^(8b) is CN andR^(8c) is H)

ESI-MS: [M+H⁺]=697.3

Example 6N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-fluoro-4-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;2,2,2-trifluoroacetic acid

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is F, R^(8b) is methoxy andR^(8c) is H)

ESI-MS: [M+H⁺]=720.2

The product was obtained in form of two conformers. These conformerswere identified via HPLC (Column: Zorbax Extended C18, 50×2.1 mm ID,1.8μ, System: Acetonitrile/Formic acid, Flow: 0.7 ml/min, Inj. Vol: 1 μlTemp: 65° C.):

-   Conformer 6A: retention time: 1.54 min-   Conformer 6B: retention time: 1.66 min

Example 7N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is methoxy, R^(8b) ismethoxy and R^(8c) is H)

ESI-MS: [M+H⁺]=732.3

The product was obtained in form of two conformers. These conformerswere identified via HPLC (Column: Zorbax Extended C18, 50×2.1 mm ID,1.8μ, System: Acetonitrile/Formic acid, Flow: 0.7 ml/min, Inj. Vol: 1 μlTemp: 65° C.):

-   Conformer 7A: retention time: 3.99 min-   Conformer 7B: retention time: 4.60 min

Example 8N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is H, R^(8b) is F andR^(8c) is H)

ESI-MS: [M+H⁺]=690.3

The product was obtained in form of two conformers. These conformerswere identified via HPLC (Column: Zorbax Extended C18, 50×2.1 mm ID,1.8μ, System: Acetonitrile/Formic acid, Flow: 0.7 ml/min, Inj. Vol: 1 μlTemp: 65° C.):

-   Conformer 8A: retention time: 3.78 min-   Conformer 8B: retention time: 4.89 min

Example 9N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-diethylaminoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(diethylamino)-ethyl, R^(8a) is H, R^(8b) is methoxy andR^(8c) is H)

9.1 N,N-Diethyl-2-(2,6-diazaspiro[3.3]heptan-2-yl)ethanaminetris(2,2,2-trifluoroacetate)

tert-Butyl6-(2-(diethylamino)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate wasdeprotected with TFA as described in step 1.3 of example 1. The productwas further reacted immediately in order to avoid degradation.

9.2N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-diethylaminoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S)-Phenyl(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamateand N,N-diethyl-2-(2,6-diazaspiro[3.3]heptan-2-yl)ethanaminetris(2,2,2-trifluoroacetate) were reacted as described in step 1.2 ofexample 1.

ESI-MS: [M+Na⁺]=710.5; [M+H⁺]=688.3;

Example 10N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;2,2,2-trifluoroacetic acid

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is H, R^(8b) is methyl andR^(8c) is H)

ESI-MS: [M+H⁺]=686.2

Example 11N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;2,2,2-trifluoroacetic acid

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is methoxy, R^(8b) is H andR^(8c) is H)

ESI-MS: [M+H⁺]=702.3

Example 12N-[(3S)-5-Cyano-1-(4-methoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;2,2,2-trifluoroacetic acid

(S-enantiomer of compound of formula I.17, wherein X¹ is NH, R¹ is CN,R² is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is H, R^(8b) is methoxyand R^(8c) is H)

The title compound was prepared from (S)-phenyl(5-cyano-1-((4-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamateas described in step 1.2 of example 1.

ESI-MS: [M+H⁺]=688.2

Example 13N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[2-(1-piperidyl)ethyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(piperidin-1-yl)-ethyl, R^(8a) is H, R^(8b) is methoxy andR^(8c) is H)

13.1 2-(2-(Piperidin-1-yl)ethyl)-2,6-diazaspiro[3.3]heptanetris(2,2,2-trifluoroacetate)

The title compounds was prepared from tert-butyl6-(2-(piperidin-1-yl)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate asdescribed in step 9.1 of example 9.

13.2(S)-N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(2-(piperidin-1-yl)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide

The title compounds was prepared from (S)-phenyl(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamate and2-(2-(piperidin-1-yl)ethyl)-2,6-diazaspiro[3.3]heptanetris(2,2,2-trifluoroacetate) as described in step 1.2 of example 1.

ESI-MS: [M+H⁺]=544.3

13.3N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[2-(1-piperidyl)ethyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide

Potassium tert-butanolate (0.08 mmol, 8 mg) was added to a solution of(S)-N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(2-(piperidin-1-yl)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxamidefrom step 13.2 (0.06 mmol, 33 mg) in THF (1.5 ml) cooled down to 0° C.;and the mixture was further stirred for 1 h at 0° C. Then4-methoxybenzene-1-sulfonyl chloride (0.07 mmol, 14 mg) was added andstirred for 12 h. The mixture was poured into cold 5% aq. K₂CO₃ (5 ml)and extracted with CH₂Cl₂ (3×5 ml). The organic phases were combined,washed with water (3×5 ml), dried on Na₂SO₄, filtered, evaporated, andfinally passed through a silicagel column (eluent: CH₂Cl₂:MeOH 9:1).Yield: 11 mg (25%).

ESI-MS: [M+H⁺]=700.3

The product was obtained in form of two conformers. These conformerswere identified via HPLC (Column: Zorbax Extended C18, 50×2.1 mm ID,1.8μ, System: Acetonitrile/Formic acid, Flow: 0.7 ml/min, Inj. Vol: 1 μlTemp: 65° C.):

-   Conformer 13A: retention time: 1.47 min-   Conformer 13B: retention time: 1.57 min

In examples 14 to 18 only one conformer was observed.

Example 14N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is methoxy, R^(8b) is H andR^(8c) is H)

14.1 tert-Butyl6-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

K₂CO₃ (52.0 mmol, 7.2 g) was added to a suspension of tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (10.4 mmol, 3.0 g) inDMF (90 ml). After 1 h stirring at rt, 4-(2-bromoethyl)morpholinehydrochloride (11.5 mmol, 2.6 g) was added portionwise and the mixturewas stirred at rt for 12 h. The precipitate was filtered off, and thefiltrate evaporated in vacuo. The residue was passed through a silicagelcolumn (eluent: CH₂Cl₂:MeOH 9:1). Yield: 1.9 g (59%).

14.2 4-(2-(2,6-Diazaspiro[3.3]heptan-2-yl)ethyl)morpholinetris(2,2,2-trifluoroacetate)

TFA (61 mmol, 4.7 ml) was added to a solution of tert-butyl6-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate from step14.1 (6.1 mmol, 1.9 g) in CH₂Cl₂ (15 ml). The mixture was stirred at rtfor 1 h, and solvents were removed under vacuo. The residue wascrystallized by addition of a few drops of diethyl ether to the solutionin MeOH. Yield: 2.2 g (65%).

14.3(S)-N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide

DIPEA (21.7 mmol, 3.8 ml) was added to a suspension of4-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl)morpholinetris(2,2,2-trifluoroacetate) from step 14.2 (4.3 mmol, 2.4 g) in CH₂Cl₂(50 ml). Once in solution,(S)-phenyl-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamate(4.3 mmol, 1.8 g) was added and the mixture was further stirred for 12h. The mixture was then poured into cold 5% aq. K₂CO₃ (50 ml) andextracted with CH₂Cl₂ (3×50 ml). The organic phases were combined,washed with water (3×50 ml), dried on Na₂SO₄, filtered and evaporated.The residue was precipitated in ether, filtered off, washed with ether,and dried in vacuo.

Yield: 2.13 g (92%).

ESI-MS: [M+H⁺]=532.2

14.4N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

The title compound was obtained in analogy to example 13 from(S)-N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxamidefrom step 14.3 and 2-methoxybenzene-1-sulfonyl chloride.

ESI-MS: [M+H⁺]=702.3 (only 1 conformer observed)

Example 15N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is methoxy, R^(8b) ismethoxy and R^(8c) is H)

The title compound was obtained in analogy to example 13 from(S)-N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxamidefrom step 14.3 and 2,4-dimethoxybenzene-1-sulfonyl chloride.

ESI-MS: [M+H⁺]=732.3 (only 1 conformer observed)

Example 16N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is H, R^(8b) is methyl andR^(8c) is H)

The title compound was obtained in analogy to example 13 from(S)-N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxamidefrom step 14.3 and 4-methylbenzene-1-sulfonyl chloride.

ESI-MS: [M+H⁺]=686.3 (1 conformer)

Example 17N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is methoxy, R^(8b) is F andR^(8c) is H)

The title compound was obtained in analogy to example 13 from(S)-N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxamidefrom step 14.3 and 4-fluoro-2-methoxybenzene-1-sulfonyl chloride.

ESI-MS: [M+H⁺]=720.3 (only 1 conformer observed)

Example 18N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-fluoro-4-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is F, R^(8b) is methoxy andR^(8c) is H)

The title compound was obtained in analogy to example 13 from(S)-N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxamidefrom step 14.3 and 2-fluoro-4-methoxybenzene-1-sulfonyl chloride.

ESI-MS: [M+H⁺]=720.3 (only 1 conformer observed)

Example 19N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-6-fluoro-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is F, R⁵ is 2-(morpholin-4-yl)-ethyl, R^(8a) is H, R^(8b) is methoxy andR^(8c) is H)

19.1 (S)-Phenyl(5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamate

Pyridine (1.5 mmol, 0.1 ml) was added to a solution of(S)-3-amino-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-((4-methoxyphenyl)sulfonyl)-2-oxoindoline-5-carbonitrile(described in WO2009/071690, 0.15 mmol, 72 mg) in CH₂Cl₂ (5 ml) cooledat 5° C. Phenyl chloroformate (0.16 mmol, 26 mg) was added dropwise andthe mixture stirred for 1 h at 0° C. The reaction was monitored by TLC(eluted with MeOH (5%)/CH₂Cl₂). The mixture was poured into cold water(5 ml) and extracted with CH₂Cl₂ (3×5 ml). The combined organic phaseswere washed with water (3×5 ml), dried on Na₂SO₄, filtered andevaporated in vacuo. The residue was used in the next step withoutfurther purification.

19.2N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-6-fluoro-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

The title compound was obtained in analogy to step 1.2 of example 1 from(S)-phenyl(5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamatefrom step 19.2 and 4-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl)morpholinetris(2,2,2-trifluoroacetate) (see step 14.2 of example 14; 0.1 mmol, 65mg).

ESI-MS: [M+H⁺]=720.30

Example 203-(2-Ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-3-[2-[2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptan-6-yl]-2-oxo-ethyl]-2-oxo-indoline-5-carbonitrile

(Compound of formula I.1, wherein X¹ is CH₂, R¹ is CN, R² is H, R⁵ is2-(morpholin-4-yl)-ethyl, R^(8a) is H, R^(8b) is methoxy and R^(8c) isH)

DIPEA (0.9 mmol, 121 mg) was added to a solution of(2-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)aceticacid (synthesis described in WO2009/071687, 0.1 mmol, 68 mg) and4-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-morpholinetris(2,2,2-trifluoroacetate) (see step 14.2 of example 14, 0.2 mmol, 89mg) in CH₂Cl₂ (20 ml). Then2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (HATU, 0.3 mmol, 127 mg) was added and themixture stirred at room temperature for 12 h. The reaction was monitoredby TLC (eluted with MeOH (5%)/CH₂Cl₂). The reaction mixture was dilutedwith CH₂Cl₂ and washed with water (20 mL each). The organic phase wasdried on Na₂SO₄, filtered and evaporated. It was passed through asilicagel column (eluent: MeOH (2%)/CH₂Cl₂). Yield: 55 mg (59%).

ESI-MS: [M+K⁺]=739.20; [M+Na⁺]=723.25; [M+H⁺]=701.20

The two enantiomers 20A and 20B were separated by chiral HPLC from theracemic title compound on following column: DAICEL Chiralpak IC 2×25 cm;flow 12 ml/min; eluent n-heptane/ethanol/triethylamine 300:700:1.

Example 21N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethoxy)-6-azaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.2, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 2-(morpholin-4-yl)-ethoxy, R^(8a) is H, R^(8b) is methoxyand R^(8c) is H)

21.1 tert-Butyl6-(2-morpholinoethoxy)-2-azaspiro[3.3]heptane-2-carboxylate

Potassium tert-butanolate (1.7 mmol, 188 mg) was added portionwise to asolution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate(1.5 mmol, 325 mg) in DMF abs. (2 ml) cooled at 0° C. After stirring for1 h at 0° C., 4-(2-bromoethyl)morpholine hydrobromide (0.7 mmol, 199 mg)was added and the mixture was stirred for 12 h at rt. It was poured ontocold NaHCO₃ conc. (5 ml) and extracted with ether (3×5 ml). The organicphases were combined and washed once with NaHCO₃ conc. (5 ml) and driedon Na₂SO₄, filtered and evaporated. The residue was passed through asilicagel column (eluent: 1.) neat EtOAc; 2.) EtOAc:MeOH 1:1). Yield:67.5 mg (27%).

21.2 4-(2-(2-Azaspiro[3.3]heptan-6-yloxy)ethyl)morpholinebis(2,2,2-trifluoroacetate)

tert-Butyl 6-(2-morpholinoethoxy)-2-azaspiro[3.3]heptane-2-carboxylatefrom step 21.1 (0.2 mmol, 66 mg) was deprotected with TFA (10 eq., 20mmol, 231 mg) in CH₂Cl₂ (5 ml) at rt for 1 h. The product was used inthe next step without further purification. Yield: 92 mg (quant).

21.3N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethoxy)-6-azaspiro[3.3]heptane-6-carboxamide

The title compound was prepared in analogy to step 1.2 of example 1 from(S)-phenyl(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamateand 4-(2-(2-azaspiro[3.3]heptan-6-yloxy)ethyl)morpholinebis(2,2,2-trifluoroacetate).

The filtrate was passed through a silicagel column (eluent: EtOAc:MeOH17:3), which afforded two conformers of the title compound. Yield:Conformer 21A: 38 mg, 27%; conformer 21B: 28 mg, 20% (85% purity).

ESI-MS: [M+H⁺]=717.40

These two conformers were identified via HPLC (Column: Zorbax ExtendedC18, 50×2.1 mm ID, 1.8μ, System: Acetonitrile/Formic acid, Flow: 0.7ml/min, Inj. Vol: 1 μl Temp: 65° C.):

-   Conformer 21A: retention time: 1.39 min-   Conformer 21B: retention time: 1.25 min

Example 22(±)-N-[5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(Compound of formula I.1, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ is1-isopropylpiperidin-4-yl, R^(8a) is methoxy, R^(8b) is methoxy andR^(8c) is H)

Zinc(II) chloride (0.01 mmol, 1.5 mg) was added to a solution of(±)-N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide2,2,2-trifluoroacetate (0.02 mmol, 15 mg) and propan-2-one (0.03 mmol,1.6 mg) in methanol (5 ml). The solution was stirred for 30 min at rt.Sodium cyanotrihydroborate (0.02 mmol, 1.4 mg) was added and the wholemixture was stirred for 2 d at rt. The reaction was monitored by TLC(eluent: 5% MeOH/CH₂Cl₂). The mixture was poured onto cold 5% aq. K₂CO₃(30 mL) and extracted three times with 20 mL ethyl acetate. The combinedorganic phases were washed with water (3×20 mL), dried on Na₂SO₄,filtered and evaporated. The crude was purified using preparative TLC(eluent: 10% MeOH/CH₂Cl₂). Yield: 5 mg (37%).

ESI-MS: [M+H⁺]=744.30

Example 23(±)-N-[5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(Compound of formula I.1, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ is1-methylpiperidin-4-yl, R^(8a) is methoxy, R^(8b) is methoxy and R^(8c)is H)

23.1 tert-Butyl6-(1-methylpiperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

Acetic acid (10.4 mmol, 0.6 ml) and sodium triacetoxyhydroborate (10.4mmol, 2.2 g, portionwise) were added to tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (1.04 mmol, 300 mg)dissolved in THF (45 ml) under N₂. The mixture was stirred overnight,poured onto 5% K₂CO₃ aq. (50 ml), then extracted with EtOAc (3×50 ml),and chloroform (3×50 ml). The organic phases were combined, dried onNa₂SO₄, filtrated and concentrated in vacuo. The product was passedthrough a silicagel column (eluent: EtOAc:MeOH: 25% NH₃ aq. 15:3:2).Yield: 123 mg (40%).

23.2 2-(1-Methylpiperidin-4-yl)-2,6-diazaspiro[3.3]heptanetrihydrochloride

tert-Butyl6-(1-methylpiperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate fromstep 23.1 (0.42 mmol, 123 mg) was dissolved in HCl (2M in diethylether,10 ml). The reaction mixture was stirred at rt for 12 h. The precipitatewas filtrated, taken up in MeOH and evaporated. Yield: 75.1 mg (92%).

23.3 (±)-Phenyl(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamate

Phenyl chloroformate (1.3 eq., 2 mmol, 309 mg) was added dropwise over10 min to a solution of3-amino-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile(1.5 mmol, 750 mg) and pyridine (15.2 mmol, 1.2 g) in CH₂Cl₂ (100 ml)cooled at 5° C. The mixture was allowed to warm up to room temperatureand stirred for 12 h. 2 additional eq. of phenyl chloroformate (3 mmol,475 mg) were added and the mixture was further stirred for 5 h at roomtemperature. The reaction was monitored by TLC eluted with 5%MeOH/CH₂Cl₂. The mixture was diluted with CH₂Cl₂ (50 ml) and water wasadded (100 ml). The phases were separated and the organic layer waswashed with sat. aq. Na₂CO₃ and water (1×200 ml), dried on Na₂SO₄,filtered and evaporated. The crude product was taken up into a smallamount of CH₂Cl₂ and treated with diisopropyl ether. The mixture wasstirred for 2 h and the precipitate filtered off and dried in vacuo (30°C.). Yield: 920 mg (quant.) ESI-MS: [M+K⁺]=653.00; [M+Na⁺]=637.10;[M+H⁺]=615.10

23.4(±)-N-[5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

Triethylamine (0.13 mmol, 13 mg) was added to a solution of2-(1-methylpiperidin-4-yl)-2,6-diazaspiro[3.3]heptane trihydrochloridefrom step 23.2 (0.04 mmol, 11 mg) and (±)-phenyl(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamatefrom step 23.3 (0.02 mmol, 10 mg) in THF (1.5 ml). The mixture wasstirred at room temperature for 12 h, poured onto cold 5% aq. K₂CO₃ andextracted three times with ethyl acetate (2 ml). The organic phases werecombined and washed with water (3×2 ml), dried on Na₂SO₄, filtered andevaporated. The residue was purified by preparative TLC (eluent: 17:3CH₂Cl₂/2M NH₃ in EtOH). Yield: 3.91 mg (34%).

ESI-MS: [M+H⁺]=716.30 (ca 90% purity)

Example 24N-[(3S)-5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 1-isopropylpiperidin4-yl, R^(8a) is H, R^(8b) is cyano andR^(8c) is H)

24.1(S)-N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(1-isopropylpiperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide

DIPEA (2.4 mmol, 0.4 ml) was added to a suspension of2-(1-isopropylpiperidin-4-yl)-2,6-diazaspiro[3.3]heptanetris(2,2,2-trifluoroacetate) (0.48 mmol, 273 mg) in CH₂Cl₂ (10 ml). Oncesolved, (S)-phenyl(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamate (0.48mmol, 200 mg) was added and the mixture was stirred for 12 h. Themixture was poured onto cold 5% aq. K₂CO₃ (10 ml) and extracted withCH₂Cl₂ (3×10 ml). The organic phases were combined, washed with water(3×10 ml) and dried with Na₂SO₄, filtered and evaporated. The residuewas passed through a silicagel column (eluent: CH₂Cl₂:2M NH₃/EtOH 1:1).Yield: 127.4 mg (49%).

24.2N-[(3S)-5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

Potassium tert-butanolate (0.06 mmol, 6 mg) was added to(S)-N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(1-isopropylpiperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamidefrom step 24.1 (0.06 mmol, 30 mg) dissolved in THF (1 ml) at 0° C. After1 h stirring at 0° C., 4-cyanobenzene-1-sulfonyl chloride (0.06 mmol, 11mg) was added and the mixture stirred for 2 d at rt. The mixture waspoured onto cold 5% aq. K₂CO₃ (5 ml) and extracted with EtOAc (3×5 ml).The organic phases were combined, washed with water (3×5 ml), dried onNa₂SO₄, filtered and evaporated. The residue was passed on a silicagelcolumn (eluent: CH₂Cl₂:2M NH₃/EtOH 17:3). Yield: 12.12 mg (31%).

ESI-MS: [M+H⁺]=709.30 (ca 90% purity)

Example 25N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 1-isopropylpiperidin-4-yl, R^(8a) is H, R^(8b) is methyl andR^(8c) is H)

The title compound was prepared in analogy to example 24 using4-methylbenzene-1-sulfonyl chloride.

ESI-MS: [M+H⁺]=698.30

Example 26N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is oxetan-3-yl, R^(8a) is H, R^(8b) is methyl and R^(8c) is H)

26.1(S)-N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide

The title compound was prepared in analogy to example 24.1 using2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane bis(2,2,2-trifluoroacetate).

ESI-MS: [M+H⁺]=475.20

26.2N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

The title compound was prepared in analogy to example 24.2 using(S)-N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamideand 4-methylbenzene-1-sulfonyl chloride.

ESI-MS: [M+H⁺]=629.30

Example 27N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 1-isopropylpiperidin-4-yl, R^(8a) is H, R^(8b) is F andR^(8c) is H)

ESI-MS: [M+H⁺]=702.30 (90% purity)

Example 28N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is oxetan-3-yl, R^(8a) is H, R^(8b) is F and R^(8c) is H)

28.1(S)-N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide2,2,2-trifluoroacetate

(S)-tert-Butyl6-((5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(0.1 mmol, 58 mg) was deprotected with TFA (20 eq., 2.2 mmol, 255 mg) inCH₂Cl₂ (10 ml). Yield: 56.3 mg (95%)

ESI-MS: [M+H⁺]=419, 20

28.2 (S)-tert-Butyl4-(6-((5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamoyl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidine-1-carboxylate

(S)-N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide2,2,2-trifluoroacetate from step 28.1 (0.09 mmol, 50 mg), tert-butyl4-oxopiperidine-1-carboxylate (0.09 mmol, 19 mg), sodium acetate (0.09mmol, 8 mg) and conc. acetic acid (2 eq., 0.19 mmol, 11 μl) weredissolved in EtOH (5 ml) and stirred for 1 h. Sodium cyanotrihydroborate(0.11 mmol, 7 mg) was added portionswise and the mixture was stirred for12 h at rt. The mixture was poured onto cold 5% aq. K₂CO₃ (5 ml) andextracted with ethyl acetate (3×5 ml). The organic phases were combined,washed with water (3×5 ml) and dried on Na₂SO₄, filtered and evaporated.Yield: 51.2 mg (91%).

ESI-MS: [M+H⁺]=602.30

28.3(S)-N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamidebis(2,2,2-trifluoroacetate)

(S)-tert-Butyl4-(6-((5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamoyl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidine-1-carboxylatefrom step 28.2 (0.08 mmol, 50 mg) was deprotected with TFA (20 eq., 1.7mmol, 190 mg) in CH₂Cl₂ (5 ml). Yield: 59.8 mg (quant.)

ESI-MS: [M+H⁺]=502.30

28.4(S)-N-(5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(1-(oxetan-3-yl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide(R-2630)

(S)-N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamidebis(2,2,2-trifluoroacetate) from step 28.3 (0.08 mmol, 58 mg),oxetan-3-one (0.08 mmol, 6 mg), sodium acetate (0.16 mmol, 13 mg) andconc. acetic acid were dissolved in EtOH (1.5 ml). The mixture wasstirred for 1 h and sodium cyanotrihydroborate (0.1 mmol, 6 mg) wasadded portionswise, and further stirred for 12 h at rt. The mixture waspoured onto cold 5% aq. K₂CO₃ (5 ml) and extracted with ethyl acetate(3×5 ml). The organic phases were combined, washed with water (3×5 ml),dried with Na₂SO₄, filtered and evaporated. Yield: 34.2 mg (77%).

ESI-MS: [M+H⁺]=558.30

28.5N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide

The title compound was prepared in analogy to example 24.2 using(S)-N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(1-(oxetan-3-yl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamideand 4-fluorobenzene-1-sulfonyl chloride.

ESI-MS: [M+H⁺]=716.30

Example 29N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 1-isopropylpiperidin-4-yl, R^(8a) is H, R^(8b) is methoxyand R^(8c) is H)

ESI-MS: [M+H+]=714.30

Example 30N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 1-(oxetan-3-yl)-piperidin-4-yl, R^(8a) is H, R^(8b) ismethyl and R^(8c) is H)

ESI-MS: [M+H⁺]=712.30 (90% purity)

Example 31N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is oxetan-3-yl, R^(8a) is H, R^(8b) is F and R^(8c) is H)

ESI-MS: [M+H⁺]=633.20

Example 32N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 1-methylpiperidin-4-yl, R^(8a) is methoxy, R^(8b) is H andR^(8c) is H)

The title compound was prepared in analogy to step 24.1 of example 24using (S)-phenyl(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((2-methoxyphenyl)sulfonyl)-2-oxo-indolin-3-yl)carbamate;ESI-MS: [M+H⁺]=686.20

The product was obtained in form of two conformers. These conformerswere identified with following column: Grace, GROM_SIL 80 ODS 7 pH, 4μm, 40×2 mm ID, System: Methanol/TFA, Flow: 0.6 ml/min, Inj. Vol: 3 μlTemp: 65° C.

-   Conformer 32A: retention time: 4.78 min-   Conformer 32B: retention time: 4.55 min

The conformers were separated via preparative HPLC with followingcolumn: xTerra prepMS C18 19×150 mm 5 μm; flow 15 ml/min; eluentgradient H₂O/10-100% MeOH+0.1% TFA

-   Conformer 32A: ESI-MS: [M+H⁺]=686.20-   Conformer 32B: ESI-MS: [M+H⁺]=686.20

Example 33N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 1-methylpiperidin-4-yl, R^(8a) is H, R^(8b) is methoxy andR^(8c) is H)

The title compound was prepared in analogy to step 24.1 of example 24using (S)-phenyl(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxo-indolin-3-yl)carbamate;ESI-MS: [M+H⁺]=686.30

The product was obtained in form of two conformers. These conformerswere identified with following column: Grace, GROM_SIL 80 ODS 7 pH, 4μm, 40×2 mm ID, System: Methanol/TFA, Flow: 0.6 ml/min, Inj. Vol: 3 μlTemp: 65° C.

-   Conformer 33A: retention time: 4.90 min-   Conformer 33B: retention time: 4.64 min

The conformers were separated via preparative HPLC with followingcolumn: xTerra prepMS C18 19×150 mm 5 μm; flow 15 ml/min; eluentgradient H₂O/10-100% MeOH+0.1% TFA

-   Conformer 33A: ESI-MS: [M+H⁺]=686.30-   Conformer 33B: ESI-MS: [M+H⁺]=686.30

Example 34N-[(3S)-1-(Benzenesulfonyl)-5-cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.1, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 1-methylpiperidin-4-yl, R^(8a) is H, R^(8b) is H and R^(8c)is H)

The title compound was prepared in analogy to step 24.1 of example 24using (S)-phenyl(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)indolin-3-yl)carbamate.

ESI-MS: [M+H⁺]=656.20

The product was obtained in form of two conformers. These conformerswere identified with following column: Macherey & Nagel Nucleosil C18PPN, 100×2.1, System: Methanol/TFA, Flow: 0.2 ml/min, Inj. Vol: 41 Temp:40° C.

-   Conformer 34A: retention time: 17.79 min-   Conformer 34B: retention time: 19.74 min

The conformers were separated via preparative HPLC with followingcolumn: xTerra prepMS C18 19×150 mm 5 μm; flow 15 ml/min; eluentgradient H₂O/10-100% MeOH+0.1% TFA

-   Conformer 34A: ESI-MS: [M+H⁺]=656.20-   Conformer 34B: ESI-MS: [M+H⁺]=656.20

Example 35N-[(3S)-5-Cyano-3-(2-ethoxyphenyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;2,2,2-trifluoroacetic acid

(S-enantiomer of compound of formula I.49, wherein X¹ is NH, R¹ is CN,R² is H, R⁵ is 1-(oxetan-3-yl)-piperidin-4-yl, R^(8a) is H, R^(8b) ismethoxy and R^(8c) is H)

ESI-MS: [M+H⁺]=727.30

The product was obtained in form of two conformers. These conformerswere identified with following column: Zorbax Extended C18, 50×2.1 mmID, 1.8μ, System: ACN/Formic acid, Flow: 0.7 ml/min, Inj. Vol: 1 μlTemp: 65° C.

-   Conformer 35A: retention time: 1.48 min-   Conformer 35B: retention time: 1.83 min

The conformers were separated via preparative RP-HPLC with followingcolumn: LUNA C18 Axia 100A 5μ 75×30; flow 40 ml/min; eluent gradientH2O/10-90% MeOH+0.1% TFA

-   Conformer 35A: ESI-MS: [M+H⁺]=727.30-   Conformer 35B: ESI-MS: [M+H⁺]=727.30

Example 36N-[(3S)-5-Cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxyphenyl)-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;2,2,2-trifluoroacetic acid

(S-enantiomer of compound of formula I.49, wherein X¹ is NH, R¹ is CN,R² is H, R⁵ is 1-(oxetan-3-yl)-piperidin-4-yl, R^(8a) is H, R^(8b) iscyano and R^(8c) is H)

ESI-MS: [M+H⁺]=722.20

Example 37N-[(3S)-5-Cyano-3-(2-ethoxyphenyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;2,2,2-trifluoroacetic acid

(S-enantiomer of compound of formula I.49, wherein X¹ is NH, R¹ is CN,R² is H, R⁵ is 1-(oxetan-3-yl)-piperidin-4-yl, R^(8a) is H, R^(8b) is Fand R^(8c) is H)

ESI-MS: [M+H⁺]=715.30

The product was obtained in form of two conformers. These conformerswere identified with following column: Zorbax Extended C18, 50×2.1 mmID, 1.8μ, System: ACN/Formic acid, Flow: 0.7 ml/min, Inj. Vol: 1 μlTemp: 65° C.

-   Conformer 37A: retention time: 1.48 min-   Conformer 37B: retention time: 1.82 min

The conformers were separated via preparative RP-HPLC with followingcolumn: LUNA C18 Axia 100A 5μ 75×30; flow 40 ml/min; eluent gradientH2O/10-90% MeOH+0.1% TFA

-   Conformer 37A: ESI-MS: [M+H⁺]=715.30-   Conformer 37B: ESI-MS: [M+H⁺]=715.30

Example 38N-[(3S)-5-Cyano-3-(2-ethoxyphenyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;2,2,2-trifluoroacetic acid

(S-enantiomer of compound of formula I.49, wherein X¹ is NH, R¹ is CN,R² is H, R⁵ is 1-(oxetan-3-yl)-piperidin-4-yl, R^(8a) is H, R^(8b) ismethyl and R^(8c) is H)

ESI-MS: [M+H⁺]=711.30

The product was obtained in form of two conformers. These conformerswere identified with following column: Zorbax Extended C18, 50×2.1 mmID, 1.8μ, System: ACN/Formic acid, Flow: 0.7 ml/min, Inj. Vol: 1 μlTemp: 65° C.

-   Conformer 38A: retention time: 1.59 min-   Conformer 38B: retention time: 1.80 min

The conformers were separated via preparative RP-HPLC with followingcolumn: LUNA C18 Axia 100A 5μ 75×30; flow 40 ml/min; eluent gradientH2O/10-90%

MeOH+0.1% TFA

-   Conformer 38A: ESI-MS: [M+H⁺]=711.30-   Conformer 38B: ESI-MS: [M+H⁺]=711.30

Example 39N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxyphenyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.49, wherein X¹ is NH, R¹ is CN,R² is H, R⁵ is 1-methylpiperidin-4-yl, R^(8a) is methoxy, R^(8b) ismethoxy and R^(8c) is H)

ESI-MS: [M+H+]=715.3

The product was obtained in form of two conformers. These conformerswere identified with following column: Phenomenex, Kinetex 1.7μ, 100A,C18, 50×2.1, System: MeOH/Formic acid, Flow: 0.6 ml/min, Inj. Vol: 2 μlTemp: 70° C.

-   Conformer 39A: retention time: 3.32 min-   Conformer 39B: retention time: 4.08 min

The conformers were separated via preparative HPLC with followingcolumn: xTerra prepMS C18 19×150 mm 5 μm; flow 15 ml/min; eluentgradient H2O/10-90% MeOH+0.1% TFA

-   Conformer 39A: ESI-MS: [M+H⁺]=715.30-   Conformer 39B: ESI-MS: [M+H⁺]=715.30

Example 40N-[(3S)-5-Cyano-3-(2-ethoxyphenyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.49, wherein X¹ is NH, R¹ is CN,R² is H, R⁵ is 1-isopropylpiperidin-4-yl, R^(8a) is H, R^(8b) is methoxyand R^(8c) is H)

ESI-MS: [M+H⁺]=713.30

Example 41N-[(3S)-5-Cyano-3-(2-ethoxyphenyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.49, wherein X¹ is NH, R¹ is CN,R² is H, R⁵ is 1-isopropylpiperidin-4-yl, R^(8a) is H, R^(8b) is methyland R^(8c) is H)

ESI-MS: [M+H⁺]=697.30

The product was obtained in form of two conformers. These conformerswere identified with following column: WATERS, XBridge C18, 2.5μ, 20×2.1mm ID, System: MeOH/Formic acid, Flow: 0.6 ml/min, Inj. Vol: 3 μl Temp:65° C.

-   Conformer 41A: retention time: 4.56 min-   Conformer 41B: retention time: 4.74 min

Example 42N-[(3S)-5-Cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxyphenyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide

(S-enantiomer of compound of formula I.49, wherein X¹ is NH, R¹ is CN,R² is H, R⁵ is 1-isopropylpiperidin-4-yl, R^(8a) is H, R^(8b) is cyanoand R^(8c) is H)

ESI-MS: [M+H⁺]=708.30

The product was obtained in form of two conformers. These conformerswere identified with following column: WATERS, XBridge C18, 2.5μ, 20×2.1mm ID, System: MeOH/Formic acid, Flow: 0.6 ml/min, Inj. Vol: 3 μl Temp:65° C.

-   Conformer 42A: retention time: 4.23 min-   Conformer 42B: retention time: 4.63 min

Example 43N-[(3S)-5-Cyano-3-(2-ethoxyphenyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;2,2,2-trifluoroacetic acid

(S-enantiomer of compound of formula I.49, wherein X¹ is NH, R¹ is CN,R² is H, R⁵ is 1-isopropylpiperidin-4-yl, R^(8a) is H, R^(8b) is F andR^(8c) is H)

The product was obtained in form of two conformers. These conformerswere separated with following RP-HPLC column: xTerra prepMS C18 19×150mm 5 μm; flow 15 ml/min; eluent gradient H₂O/30-100% MeOH+0.1% TFA

-   Conformer 43A: retention time: 14.27 min-   Conformer 43B: retention time: 18.36 min

Example 44N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-azaspiro[3.3]heptane-2-carboxamide

(S-enantiomer of compound of formula I.3, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is H, R^(8a) is H, R^(8b) is methoxy and R^(8c) is H)

44.1 (S)-tert-Butyl6-((5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate

N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (5.4 mmol, 1.0 g) was added portionwise to a solution of(S)-3-amino-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindoline-5-carbonitrile(1.1 mmol, 500 mg) and2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (1.1mmol, 260 mg) in pyridine (10 ml). The mixture was stirred for 12 h atrt. The reaction was monitored by TLC (eluent: 5% MeOH/CH₂Cl₂). Themixture was poured onto cooled water and the precipitate filtered off.It was washed with cold water and dried in vacuo. The crude product wasdirectly used in the next step without purification.

ESI-MS: [M+H⁺]=688.20 (90% purity)

44.2N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-azaspiro[3.3]heptane-2-carboxamide

(S)-tert-Butyl6-((5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate(1.0 mmol, 679 mg) was dissolved in CH₂Cl₂ (10 ml) and then treated withTFA (9.9 mmol, 0.8 ml). The mixture was stirred at room temperature for2 h. The reaction was monitored by TLC (eluent: 5% MeOH/CH₂Cl₂). Themixture was concentrated, diluted with ethyl acetate (30 mL) and washedtwice with water (20 mL each). The combined organic layers were dried(Na₂SO₄), filtered and evaporated. The residue was purified using aSiOH-Chromabond (eluent: 0-6% MeOH/CH₂Cl₂). Yield: 114 mg (20%).

ESI-MS: [M+H⁺]=588.20

Example 45N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-(1-isopropyl-4-piperidyl)-6-azaspiro[3.3]heptane-2-carboxamide

(S-enantiomer of compound of formula I.3, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 1-isopropylpiperidin-4-yl, R^(8a) is H, R^(8b) is methoxyand R^(8c) is H)

ESI-MS: [M+H⁺]=713.35

Example 46N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-(1-methylazetidin-3-yl)-6-azaspiro[3.3]heptane-2-carboxamide

(S-enantiomer of compound of formula I.3, wherein X¹ is NH, R¹ is CN, R²is H, R⁵ is 1-methylazetidin-3-yl, R^(8a) is H, R^(8b) is methoxy andR^(8c) is H)

ESI-MS: [M+H⁺]=657.20

Example 47N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(piperidin-4-yl)-3-azaspiro[5.5]undecane-9-carboxamide2,2,2-trifluoroacetate

(Compound of formula I.15, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ ispiperidin-4-yl, R^(8a) is methoxy, R^(8b) is methoxy and R^(8c) is H)

ESI-MS: 757.30 [M+H]⁺

Example 48N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)spiro[3.3]heptane-2-carboxamide2,2,2-trifluoroacetate

(Compound of formula I.4, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ is2,6-diazaspiro[3.3]heptane-2-yl, R^(8a) is methoxy, R^(8b) is methoxyand R^(8c) is H)

ESI-MS: 713.30 [M+H]⁺

Example 49A First stereoisomer ofN-(5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-7-(piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxamide2,2,2-trifluoroacetate

(First stereoisomer of compound of formula I.5, wherein X¹ is NH, R¹ isCN, R² is H, R⁵ is piperidin-4-yl, R^(8a) is methoxy, R^(8b) is methoxyand R^(8c) is H)

ESI-MS: 730.30 [M+H]⁺

Example 49B Second stereoisomer ofN-(5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-7-(piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxamide2,2,2-trifluoroacetate

(Second stereoisomer of compound of formula I.5, wherein X¹ is NH, R¹ isCN, R² is H, R⁵ is piperidin-4-yl, R^(8a) is methoxy, R^(8b) is methoxyand R^(8c) is H)

ESI-MS: 730.30 [M+H]+

Example 50N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-2-(piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxamidebis-2,2,2-trifluoroacetate

(Compound of formula I.9, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ ispiperidin-4-yl, R^(8a) is methoxy, R^(8b) is methoxy and R^(8c) is H)

ESI-MS: 730.30 [M+H]⁺

Example 51N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-2,7-diazaspiro[3.5]nonane-7-carboxamide2,2,2-trifluoroacetate

(Compound of formula I.9, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ is H,R^(8a) is methoxy, R^(8b) is methoxy and R^(8c) is H)

ESI-MS: 647.20 [M+H]⁺

Example 52N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-azaspiro[5.5]undecane-9-carboxamide2,2,2-trifluoroacetate

(Compound of formula I.15, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ is H,R^(8a) is methoxy, R^(8b) is methoxy and R^(8c) is H)

ESI-MS: 674.30 [M+H]⁺

Example 53N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-9-methyl-3,9-diazaspiro[5.5]undecane-3-carboxamide2,2,2-trifluoroacetate

(Compound of formula I.13, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ ismethyl, R^(8a) is methoxy, R^(8b) is methoxy and R^(8c) is H)

ESI-MS: 689.30 [M+H]⁺

Example 54N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(4-ethylpiperazin-1-yl)spiro[3.3]heptane-2-carboxamide2,2,2-trifluoroacetate

(Compound of formula I.4, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ is4-ethylpiperazin-1-yl, R^(8a) is methoxy, R^(8b) is methoxy and R^(8c)is H)

ESI-MS: 729.20 [M+H]⁺

Example 55N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxamide2,2,2-trifluoroacetate

(Compound of formula I.5, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ ismethyl, R^(8a) is methoxy, R^(8b) is methoxy and R^(8c) is H)

ESI-MS: 661.20 [M+H]⁺

Example 56N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-9-ethyl-3,9-diazaspiro[5.5]undecane-3-carboxamide2,2,2-trifluoroacetate

(Compound of formula I.13, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ isethyl, R^(8a) is methoxy, R^(8b) is methoxy and R^(8c) is H)

ESI-MS: 703.20 [M+H]⁺

Example 57N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide2,2,2-trifluoroacetate

(Compound of formula I.3, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ is H,R^(8a) is methoxy, R^(8b) is methoxy and R^(8c) is H)

ESI-MS: 618.20 [M+H]⁺

Example 58N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide2,2,2-trifluoroacetate

(Compound of formula I.1, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ is H,R^(8a) is methoxy, R^(8b) is methoxy and R^(8c) is H)

ESI-MS: 619.20 [M+H]⁺

Example 59N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide2,2,2-trifluoroacetate

(Compound of formula I.1, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ ispiperidin-4-yl, R^(8a) is methoxy, R^(8b) is methoxy and R^(8c) is H)

ESI-MS: 702.30 [M+H]⁺

Example 60N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxamide2,2,2-trifluoroacetate

(Compound of formula I.5, wherein X¹ is NH, R¹ is CN, R² is H, R⁵ is H,R^(8a) is methoxy, R^(8b) is methoxy and R^(8c) is H)

ESI-MS: 647.20 [M+H]⁺

III. Determination of the Biological Activity

1. Vasopressin V1b Receptor Binding Assay:

Substances:

The test substances were dissolved in a concentration of 5 mM in 100%DMSO and further diluted to 5×10⁻⁴ M to 5×10⁻⁹ M. These serial DMSOpredilutions were diluted 1:10 with assay buffer. The substanceconcentration was further diluted 1:5 in the assay mixture resulting in2% DMSO in the mixture. All dilutions were performed in a Biomek NXautomation workstation (Beckman)

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1b receptor (clone3H2) were harvested and homogenized in 50 mM Tris-HCl and in thepresence of protease inhibitors (Roche complete Mini #1836170) using aPolytron homogenizer at intermediate setting for 2×10 seconds, andsubsequently centrifuged at 40 000×g for 1 h. The membrane pellet wasagain homogenized and centrifuged as described and subsequently taken upin 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen inliquid nitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (200 μl), membranes (26 μg protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1b receptors(cell line hV1b_3H2_CHO) were incubated with 1.5 nM ³H-AVP(8-Arg-vasopressin, PerkinElmer, NET 800) in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionallywith increasing concentrations of test substance (displacementexperiment). The nonspecific binding was determined with 1 μM AVP (Fluka94836). All determinations were carried out as duplicate determinations.After incubation (60 minutes at room temperature), the free radioligandwas filtered off by vacuum filtration (Tomtec Mach III) through WathmanGF/B glass fiber filter plates (UniFilter, PerkinElmer 6005177). Theliquid scintillation measurement took place in a Microbeta TriLux 12(Wallac).

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ³H-AVP for the recombinant human V1b receptors is 0.4nM and was used to determine the Ki.

2. Vasopressin V1a Receptor Binding Assay:

Substances:

The test substances were dissolved in a concentration of 5 mM M in DMSO.Further dilution of these DMSO solutions took place as described forV1b.

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1a receptor (clone5) were harvested and homogenized in 50 mM Tris-HCl and in the presenceof protease inhibitors (Roche complete Mini #1836170) using a Polytronhomogenizer at intermediate setting for 2×10 seconds, and subsequentlycentrifuged at 40 000×g for 1 h. The membrane pellet was againhomogenized in a High-Pressure-Homogenizer, Polytec 50K at 1500 PSI(Heinemann, Germany) and subsequently taken up in 50 mM Tris-HCl, pH7.4, homogenized and stored in aliquots frozen in liquid nitrogen at−190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (200 μl), membranes (40 μg protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1a receptors(cell line hV1a_5_CHO) were incubated with 0.04 nM ¹²⁵I-AVP(8-Arg-vasopressin, PerkinElmer NEX 128) in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionallywith increasing concentrations of test substance (displacementexperiment). The nonspecific binding was determined with 1 μM AVP (Fluka94836). Duplicate determinations were carried out.

After incubation (60 minutes at room temperature), the samples wereprocessed as described for V1b.

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ¹²⁵I-AVP for the recombinant hV1a receptors wasdetermined in saturation experiments. A Kd of 1.33 nM was used todetermine the Ki.

3. Oxytocin Receptor Binding Assay

Substances:

The substances were dissolved in a concentration of 5 mM in DMSO anddiluted further as described for V1b.

Membrane Preparation:

Confluent HEK-293 cells with transiently expressing recombinant humanoxytocin receptors were centrifuged at 750×g at room temperature for 5minutes. The residue was taken up in ice-cold lysis buffer (50 mMTris-HCl, 10% glycerol, pH 7.4 and Roche complete protease inhibitor)and subjected to an osmotic shock at 4° C. for 20 minutes. Cell lysateswere then centrifuged at 750×g at 4° C. for 20 minutes, the residue wastaken up in incubation buffer (50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH7.4), and aliquots corresponding to 10⁷ cells/ml were prepared. Thealiquots were frozen at −80° C. until use.

Binding Assay:

On the day of the experiment, the cell lysate was thawed, homogenized,and diluted with incubation buffer (50 mM Tris, 10 mM MgCl₂, 0.1% BSA,pH 7.4) to the desired concentration. The reaction mixture of 0.200 mlwas composed of cell lysate corresponding to 5×10⁴ cells (HEK-293 cellsexpressing transiently human OT receptors) and 1 nM 3H-oxytocin(PerkinElmer NET858) in the presence of test substance (displacementexperiment) or incubation buffer only (total binding). The nonspecificbinding was determined in the presence of 1 μM oxytocin (Bachem AG,H2510). Determinations were carried out in duplicates. After 60 minutesincubation at room temperature, bound and free radioligand wereseparated by filtration under vacuum on GF/B UniFilter plates (PerkinElmer #6005177) pre-incubated with 0.3% PEI. The bound radioactivity wasdetermined by liquid scintillation measurement in a Microbeta (PerkinElmer) plate counter.

Analysis:

The binding parameters were calculated by nonlinear regression analysis(SAS) in analogy to the LIGAND program of Munson and Rodbard (AnalyticalBiochem 1980; 107: 220-239). The Kd of ³H-oxytocin for the recombinanthuman OT receptors was 7.6 nM and was used to calculate the Ki fromcompetition binding experiments.

4. Determination of the Microsomal Half-life:

The metabolic stability of the compounds of the invention was determinedin the following assay.

The test substances were incubated in a concentration of 0.5 μM asfollows:

0.5 μM test substance are preincubated together with liver microsomesfrom different species (from rat, human or other species) (0.25 mg ofmicrosomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 inmicrotiter plates at 37° C. for 5 min. The reaction is started by addingNADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50 μl aliquots areremoved, and the reaction is immediately stopped and cooled with thesame volume of acetonitrile. The samples are frozen until analyzed. Theremaining concentration of undegraded test substance is determined byMSMS. The half-life (T½) is determined from the gradient of the signalof test substance/unit time plot, it being possible to calculate thehalf-life of the test substance, assuming first order kinetics, from thedecrease in the concentration of the compound with time. The microsomalclearance (mCl) is calculated from mCl=ln 2/T½/(content of microsomalprotein in mg/ml)×1000 [ml/min/mg] (modified from references: Di, TheSociety for Biomolecular Screening, 2003, 453-462; Obach, D M D, 1999vol 27. N 11, 1350-1359).

5. Methods for in vitro Determination of the Cytochrome P450 (CYP)Inhibition

Luminescent Substrates for 2C9 and 3A4:

0.4 mg/ml human liver microsomes are preincubated with the testsubstances to be investigated (0-20 μM), the CYP-specific substrates, in0.05 M potassium phosphate buffer of pH 7.4 at 37° C. for 10 min. TheCyp-specific substrate for CYP 2C9 is luciferin H, and for CYP 3A4 isluciferin BE. The reaction is started by adding NADPH. After incubationat RT for 30 min, the luciferin detection reagent is added, and theresulting luminescence signal is measured (modified from reference:Promega, Technical Bulletin P450-GLO™ Assays).

Midazolam CYP 3A4 Time-dependent Inhibition

The assay consists of 2 parts. Firstly, the test substance ispreincubated with the liver microsomes (with NADPH=preincubation, thenaddition of the substrate; in the second part the substrate and the testsubstance are added simultaneously=coincubation.

Preincubation:

0.05 mg/ml microsomal protein (human liver microsomes) are preincubatedwith 0-10 μM (or 50 μM) test substance in 50 mM potassium phosphatebuffer for 5 min. The reaction is started with NADPH. After 30 min 4 μMmidazolam (final concentration) are added, and incubation is continuedfor 10 min. 75 μl of the reaction solution are removed after 10 min, andstopped with 150 μl of acetonitrile solution.

Coincubation:

0.05 mg/ml microsomal protein (human liver microsomes) are preincubatedwith 4 μm midazolam (final concentration) and 0-10 μM (or 50 μM) testsubstance in 50 mM potassium phosphate buffer for 5 min. The reaction isstarted with NADPH. 75 μl of the reaction solution are removed after 10min and stopped with 150 μl of acetonitrile solution. The samples arefrozen until the MSMS analysis (modified from references: Obdach,Journal of Pharmacology & Experimental Therapeutics, Vol 316, 1,336-348, 2006; Walsky, Drug Metabolism and Disposition Vol 32, 6,647-660, 2004).

6. Method for Determining the Solubility in Water (in mg/ml)

The solubility in water of the compounds of the invention can bedetermined for example by the so-called shake flask method (as specifiedin ASTM International: E 1148-02, Standard test methods for measurementof aqueous solubility, Book of Standards Volume 11.05.). This entails anexcess of the solid compound being put into a buffer solution with aparticular pH (for example phosphate buffer of pH 7.4), and theresulting mixture being shaken or stirred until equilibrium has been setup (typically 24 or 48 hours, sometimes even up to 7 days). Theundissolved solid is then removed by filtration or centrifugation, andthe concentration of the dissolved compound is determined by UVspectroscopy or high pressure liquid chromatography (HPLC) by means ofan appropriate calibration plot.

7. Results

The results of the receptor binding investigations are expressed asreceptor binding constants [K_(i)(V1b)] or selectivities[K_(i)(V1a)/K_(i)(V1b)]. The results of the investigation of themetabolic stability are indicated as microsomal clearance (mCl).

The compounds of the invention show very high affinities for the V1breceptor in these assays (maximally 100 nM, or maximally 10 nM,frequently <1 nM). The compounds also show high selectivities vis-à-visthe V1a receptor and a good metabolic stability, measured as microsomalclearance.

The results are listed in table C. The numbers of the compounds refer tothe synthesis examples.

TABLE C Example K_(i)(h-V1b)* [nM] K_(i)(h-V1a)/K_(i)(h-V1b)  1 ++ +++ 1B +++ +++  2 + +++  3 ++ +++  4 ++ +++  5 + +++  6 ++ ++  7 ++ ++  8 +++  9 ++ +++ 10 ++ ++ 11 ++ +++ 12 ++ + 13 +++ ++ 14 + +++ 15 +++ +++ 16++ ++ 17 ++ ++ 18 +++ +++ 19 ++ +++ 20 ++ ++ 20A ++ ++ 21A + +++ 21B ++++ 22 ++ +++ 24 + +++ 25 + ++ 27 + +++ 29 ++ +++ 31 + 32 + ++ 33 + ++35B + ++ 39B + ++ 40 ++ +++ 41 + +++ 42 + +++ 43B + +++ 44 + 45 + + 46++ + 47 ++ 48 ++ 50 + 51 + 52 ++ 53 + 54 +++ 55 + 56 + 57 + 58 + ++ 59 ++++ 60 ++ ++ *h = humanKey:

K_(i)(h-V1b) K_(i)(h-V1a)/K_(i)(h-V1b) + >10-100 nM 10-<25 ++ 1-10 nM25-75  +++ <1 nM >75

The invention claimed is:
 1. A compound of formula I

wherein A is a ring selected from the group consisting of phenyl and6-membered hetaryl containing 1 or 2 nitrogen atoms as ring members,where ring A carries one substituent R⁶ and optionally one substituentR⁷; B is a ring selected from the group consisting of phenyl, pyridyland quinolinyl, where ring B may carry 1, 2 or 3 substituents R⁸; X¹ isNH, CH₂ or O; X² is N or CH; X³, X⁴, X⁵ and X⁶, independently of eachother, are selected from the group consisting of —CH₂—, —O—, —S(O)_(c)—,—NH—, —C(O)—, —CH₂CH₂—, —CH₂O—, —OCH₂—, —S(O)_(c)CH₂—, —CH₂S(O)_(c)—,CH₂NH—, —NHCH₂—, —CH₂C(O)— and —C(O)CH₂—; X⁷ is NH, CH₂ or O; R¹ isselected from the group consisting of cyano, halogen, C₁-C₃-alkyl,fluorinated C₁-C₃-alkyl, C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl,C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy; R² is selected from the groupconsisting of hydrogen, cyano, halogen, C₁-C₃-alkyl, fluorinatedC₁-C₃-alkyl, C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl,C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy; R³ and R⁴, independently ofeach other and independently of each occurrence, are selected from thegroup consisting of hydroxyl, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₃-C₆-cycloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and NR⁹R¹⁰, and in casethat R³ or R⁴ are bound to a carbon ring atom, are additionally selectedfrom halogen; or two non-geminal radicals R³ form together a group—(CH₂)_(k)—, where k is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms inthis group may be replaced by a methyl group; or two non-geminalradicals R⁴ form together a group —(CH₂)_(k)—, where k is 1, 2, 3 or 4,where 1 or 2 hydrogen atoms in this group may be replaced by a methylgroup; or two geminal radicals R³ form together a group —(CH₂)_(j)—,where j is 2, 3, 4 or 5, where 1 or 2 hydrogen atoms in this group maybe replaced by a methyl group; or two geminal radicals R⁴ form togethera group —(CH₂)_(j)—, where j is 2, 3, 4 or 5, where 1 or 2 hydrogenatoms in this group may be replaced by a methyl group; with the provisothat R³ and R⁴ are not halogen, hydroxyl, C₁-C₄-alkoxy orC₁-C₄-haloalkoxy if they are bound to a carbon atom in α-position to anitrogen ring atom; R⁵ is selected from the group consisting ofhydrogen; cyano; C₁-C₆-alkyl; C₂-C₆-alkenyl; C₂-C₆-alkynyl;C₃-C₇-cycloalkyl, where the four last-mentioned radicals may bepartially or fully halogenated and/or may carry one or more substituentsR¹¹; phenyl which may carry 1, 2 or 3 substituents R¹²; a 3-, 4-, 5-, 6-or 7-membered saturated, partially unsaturated or maximally unsaturatedheteromonocyclic ring containing 1, 2 or 3 heteroatoms or heteroatomgroups selected from the group consisting of O, N, S, NO, SO and SO₂ asring members; and a 5-, 6-, 7-, 8-, 9-, 10- or 11-membered saturated,partially unsaturated or maximally unsaturated heterobicyclic ringcontaining 1, 2 or 3 heteroatoms or heteroatom groups selected from thegroup consisting of O, N, S, NO, SO and SO₂ as ring members, where theheteromonocyclic or heterobicyclic ring may carry 1, 2 or 3 substituentsR¹²; —OR¹³; —S(O)₁R¹³; NR¹⁴R¹⁵; and —C(═O)R¹⁶; R⁶ and R⁷, independentlyof each other, are selected from the group consisting of halogen, cyano,hydroxyl, C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl,C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy; each R⁸ is independentlyselected from the group consisting of halogen, cyano, hydroxyl,C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxyand fluorinated C₁-C₃-alkoxy; R⁹ and R¹⁰, independently of each other,are selected from the group consisting of hydrogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₄-alkyl, phenyland benzyl; each R¹¹ is independently selected from the group consistingof cyano; —OR¹³; —S(O)₁R¹³; NR¹⁴R¹⁵; —C(═O)R¹⁶; C₃-C₆-cycloalkyl;C₃-C₆-halocycloalkyl; phenyl which may carry 1, 2 or 3 substituents R¹²;a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated ormaximally unsaturated heteromonocyclic ring containing 1, 2 or 3heteroatoms or heteroatom groups selected from the group consisting ofO, N, S, NO, SO and SO₂ as ring members; and a 5-, 6-, 7-, 8-, 9-, 10-or 11-membered saturated, partially unsaturated or maximally unsaturatedheterobicyclic ring containing 1, 2 or 3 heteroatoms or heteroatomgroups selected from the group consisting of O, N, S, NO, SO and SO₂ asring members, where the heteromonocyclic or heterobicyclic ring maycarry 1, 2 or 3 substituents R¹²; and as a substituent on a cycloalkylring, R¹¹ is additionally selected from C₁-C₄-alkyl or C₁-C₄-haloalkyl;each R¹² is independently selected from the group consisting of halogen;hydroxyl; cyano; nitro; C₁-C₄-alkyl; C₁-C₄-haloalkyl; C₃-C₆-cycloalkyl;C₃-C₆-halocycloalkyl; C₁-C₄-alkoxy; C₁-C₄-haloalkoxy; C₁-C₄-alkylthio;C₁-C₄-haloalkylthio; C₁-C₄-alkylsulfinyl; C₁-C₄-haloalkylsulfinyl;C₁-C₄-alkylsulfonyl; C₁-C₄-haloalkylsulfonyl; phenyl; phenoxy;benzyloxy, where the phenyl moiety in the three last-mentioned radicalsmay carry 1, 2 or 3 substituents selected from the group consisting ofhalogen, hydroxyl, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy andC₁-C₄-haloalkoxy; and a 3-, 4-, 5-, 6- or 7-membered saturated,partially unsaturated or maximally unsaturated heteromonocyclic ringcontaining 1, 2 or 3 heteroatoms or heteroatom groups selected from thegroup consisting of O, N, S, NO, SO and SO₂ as ring members, where theheteromonocyclic ring may carry 1, 2 or 3 substituents selected from thegroup consisting of halogen, hydroxyl, cyano, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy; each R¹³ isindependently selected from the group consisting of hydrogen;C₁-C₄-alkyl; C₁-C₄-haloalkyl; C₁-C₄-alkyl which carries one substituentR¹⁷; C₂-C₄-alkenyl; C₂-C₄-haloalkenyl; C₂-C₄-alkynyl; C₂-C₄-haloalkynyl;C₃-C₆-cycloalkyl; C₃-C₆-halocycloalkyl; phenyl which may carry 1, 2 or 3substituents selected from the group consisting of halogen, hydroxyl,cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy;and a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated ormaximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatomsor heteroatom groups selected from the group consisting of O, N, S, NO,SO and SO₂ as ring members, where the heterocyclic ring may carry 1, 2or 3 substituents selected from the group consisting of halogen,hydroxyl, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy andC₁-C₄-haloalkoxy; R¹⁴ and R¹⁵, independently of each other andindependently of each occurrence, are selected from the group consistingof hydrogen; C₁-C₄-alkyl; C₁-C₄-haloalkyl; C₃-C₆-cycloalkyl;C₃-C₆-halocycloalkyl; phenyl which may carry 1, 2 or 3 substituentsselected from the group consisting of halogen, hydroxyl, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy; and a3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated ormaximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatomsor heteroatom groups selected from the group consisting of O, N, S, NO,SO and SO₂ as ring members, where the heterocyclic ring may carry 1, 2or 3 substituents selected from the group consisting of halogen,hydroxyl, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy andC₁-C₄-haloalkoxy, C₁-C₄-alkylcarbonyl and C₁-C₄-haloalkylcarbonyl; eachR¹⁶ is independently selected the group consisting of from hydrogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl,phenyl, —OR¹³ and NR¹⁴R¹⁵; each R¹⁷ is independently selected from thegroup consisting of cyano; hydroxyl; C₁-C₄-alkoxy; C₁-C₄-haloalkoxy;C₁-C₄-alkylthio; C₁-C₄-haloalkylthio; C₁-C₄-alkylsulfinyl;C₁-C₄-haloalkylsulfinyl; C₁-C₄-alkylsulfonyl; C₁-C₄-haloalkylsulfonyl;NR¹⁴R¹⁵; C₁-C₄-alkylcarbonyl; C₁-C₄-haloalkylcarbonyl; C₃-C₆-cycloalkyl;C₃-C₆-halocycloalkyl; phenyl which may carry 1, 2 or 3 substituents R¹²;a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated ormaximally unsaturated heteromonocyclic ring containing 1, 2 or 3heteroatoms or heteroatom groups selected from the group consisting ofO, N, S, NO, SO and SO₂ as ring members; and a 5-, 6-, 7-, 8-, 9-, 10-or 11-membered saturated, partially unsaturated or maximally unsaturatedheterobicyclic ring containing 1, 2 or 3 heteroatoms or heteroatomgroups selected from the group consisting of O, N, S, NO, SO and SO₂ asring members, where the heteromonocyclic or heterobicyclic ring maycarry 1, 2 or 3 substituents R¹²; a is 0, 1 or 2; b is 0, 1 or 2; c is0, 1 or 2; and l is 0, 1 or 2; or an N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, or wherein at least one of theatoms has been replaced by its stable, non-radioactive isotope.
 2. Thecompound as claimed in claim 1, wherein at least one hydrogen atom hasbeen replaced by a deuterium atom.
 3. The compound as claimed in claim1, where X¹ is NH or CH₂.
 4. The compound as claimed in claim 1, whereX³, X⁴, X⁵ and X⁶, independently of each other, are selected from thegroup consisting of —CH₂— and —CH₂CH₂—.
 5. The compound as claimed inclaim 1, where X⁷ is NH or CH₂.
 6. The compound as claimed in claim 1,where R⁵ is bound to X⁷.
 7. The compound as claimed in claim 1, where Ais phenyl or pyridyl, where A carries one substituent R⁶ and optionallyone substituent R⁷.
 8. The compound as claimed in claim 7, where A isphenyl or 3-pyridyl, where A carries the radical R⁶ in 2-position andthe radical R⁷, if present, in 4- or 5-position, relative to the1-position of the attachment point of A to the remainder of themolecule.
 9. The compound as claimed in claim 7, where A is phenyl or3-pyridyl, where A carries the radical R⁶ in 2-position and no radicalR⁷.
 10. The compound as claimed in claim 1, where B is phenyl or2-pyridyl, where B may carry 1, 2 or 3 substituents R⁸.
 11. The compoundas claimed in claim 1, where R¹ is halogen or cyano.
 12. The compound asclaimed in claim 11, where R¹ is selected from the group consisting ofcyano, fluorine and chlorine.
 13. The compound as claimed in claim 1,where R² is hydrogen or halogen.
 14. The compound as claimed in claim 1,where R³ and R⁴, independently of each other and independently of eachoccurrence, are selected from the group consisting of halogen andC₁-C₄-alkyl, with the proviso that R³ and R⁴ are not halogen if they arebound to a carbon atom in α-position to a nitrogen ring atom.
 15. Thecompound as claimed in claim 1, where R⁵ is selected from the groupconsisting of hydrogen; C₁-C₆-alkyl; fluorinated C₁-C₆-alkyl;C₃-C₆-cycloalkyl; fluorinated C₃-C₆-cycloalkyl; C₁-C₆-alkyl whichcarries one substituent R¹¹; phenyl which may carry 1, 2 or 3substituents R¹²; a 3-, 4-, 5-, 6- or 7-membered saturated, partiallyunsaturated or maximally unsaturated heteromonocyclic ring containing 1,2 or 3 heteroatoms or heteroatom groups selected from the groupconsisting of O, N, S, NO, SO and SO₂ as ring members; and a 5-, 6-, 7-,8-, 9-, 10- or 11-membered saturated, partially unsaturated or maximallyunsaturated heterobicyclic ring containing 1, 2 or 3 heteroatoms orheteroatom groups selected from the group consisting of O, N, S, NO, SOand SO₂ as ring members, where the heteromonocyclic or heterobicyclicring may carry 1, 2 or 3 substituents R¹²; and in case that R⁵ is boundto a carbon ring atom, it is additionally selected from —OR¹³.
 16. Thecompound as claimed in claim 15, where R⁵ is selected from the groupconsisting of hydrogen; C₁-C₆-alkyl; fluorinated C₁-C₆-alkyl;C₁-C₆-alkyl which carries one substituent R¹¹; a 3-, 4-, 5- or6-membered saturated heteromonocyclic ring containing 1 or 2 heteroatomsor heteroatom groups selected from the group consisting of O, N, S, NO,SO and SO₂ as ring members; and a 7-, 8-, 9-, 10- or 11-memberedsaturated heterobicyclic ring containing 1 or 2 heteroatoms orheteroatom groups selected from the group consisting of O, N, S, NO, SOand SO₂ as ring members, where the heteromonocyclic or heterobicyclicring may carry 1, 2 or 3 substituents R¹²; and in case that R⁵ is boundto a carbon ring atom, it is additionally selected from —OR¹³.
 17. Thecompound as claimed in claim 16, where R⁵ is selected from the groupconsisting of hydrogen; C₁-C₄-alkyl; C₁-C₄-alkyl which carries onesubstituent R¹¹; a 4-, 5- or 6-membered saturated heteromonocyclic ringcontaining 1 or 2 heteroatoms selected from the group consisting of O, Nand S as ring members; and a 7-, 8-, 9-, 10- or 11-membered saturatedheterobicyclic spiro ring containing 1 or 2 heteroatoms selected fromthe group consisting of O, N and S as ring members, where theheteromonocyclic or heterobicyclic ring may carry 1 or 2 substituentsR¹²; and in case that R⁵ is bound to a carbon ring atom, it isadditionally selected from —OR¹³.
 18. The compound as claimed in claim1, where R¹¹ is selected from the group consisting of cyano; —OR¹³;NR¹⁴R¹⁵; a 3-, 4-, 5-, 6- or 7-membered saturated heteromonocyclic ringcontaining 1, 2 or 3 heteroatoms or heteroatom groups selected from thegroup consisting of O, N, S, NO, SO and SO₂ as ring members; and a 5-,6-, 7-, 8-, 9-, 10- or 11-membered saturated heterobicyclic ringcontaining 1, 2 or 3 heteroatoms or heteroatom groups selected from thegroup consisting of O, N, S, NO, SO and SO₂ as ring members, where theheteromonocyclic or heterobicyclic ring may carry 1, 2 or 3 substituentsR¹²; and as a substituent on a cycloalkyl ring, R¹¹ is additionallyselected from the group consisting of C₁-C₄-alkyl and C₁-C₄-haloalkyl.19. The compound as claimed in claim 18, where R¹¹ is NR¹⁴R¹⁵, where R¹⁴and R¹⁵ are independently selected from the group consisting of hydrogenand C₁-C₄-alkyl; or a 4-,5- or 6-membered saturated heteromonocyclicring containing 1 or 2 heteroatoms or heteroatom groups selected fromthe group consisting of O, N, S, NO, SO and SO₂ as ring members, wherethe heteromonocyclic ring may carry 1 or 2 or 3 substituents R¹². 20.The compound as claimed in claim 1, where R¹² is selected from the groupconsisting of halogen; cyano; C₁-C₄-alkyl; fluorinated C₁-C₄-alkyl;C₁-C₄-alkoxy; fluorinated C₁-C₄-alkoxy; phenyl which may carry 1, 2 or 3substituents selected from the group consisting of halogen, hydroxyl,cyano, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy andfluorinated C₁-C₄-alkoxy; and a 3-, 4-, 5- or 6-membered saturatedheteromonocyclic ring containing 1, 2 or 3 heteroatoms or heteroatomgroups selected from the group consisting of O, N, S, NO, SO and SO₂ asring members, where the heteromonocyclic ring may carry 1, 2 or 3substituents selected from the group consisting of halogen, hydroxyl,cyano, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy andfluorinated C₁-C₄-alkoxy.
 21. The compound as claimed in claim 20, whereR¹² is selected from the group consisting of C₁-C₄-alkyl, fluorinatedC₁-C₄-alkyl, and a 3-, 4-, 5- or 6-membered saturated heteromonocyclicring containing 1 or 2 heteroatoms selected from the group consisting ofO, N and S as ring members.
 22. The compound as claimed in claim 1,where R¹³ is selected from the group consisting of hydrogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl and C₁-C₄-alkyl which carries onesubstituent R¹⁷.
 23. The compound as claimed in claim 1, where R¹⁷ isselected from NR¹⁴R¹⁵; phenyl which may carry 1, 2 or 3 substituentsR¹²; and a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturatedor maximally unsaturated heteromonocyclic ring containing 1, 2 or 3heteroatoms or heteroatom groups selected from the group consisting ofO, N, S, NO, SO and SO₂ as ring members.
 24. The compound as claimed inclaim 1, where R⁶ is C₁-C₃-alkoxy.
 25. The compound as claimed in claim1, where R⁷ is halogen or C₁-C₃-alkoxy.
 26. The compound as claimed inclaim 1, where each R⁸ is independently selected from the groupconsisting of halogen, cyano, C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl,C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy.
 27. The compound as claimedin claim 26, where each R⁸ is independently selected from the groupconsisting of fluorine, cyano, methyl, methoxy and trifluoromethoxy. 28.The compound as claimed in claim 1, where a and b are independently 0or
 1. 29. The compound as claimed in claim 1, of formula IA

where X¹, X², X⁷, R¹, R², R³, R⁴, R⁵, R⁶, a and b are as defined inclaim 1; X⁸ is N or CH; X⁹ is N or C—R^(8a); R^(7a) and R^(7b),independently of each other, are hydrogen or have one of the definitionsgiven for R⁷ in claim 1, with the proviso that at least one of R^(7a)and R^(7b) is hydrogen; R^(8a), R^(8b) and R^(8c), independently of eachother, are hydrogen or have one of the definitions given for R⁸ in claim1; and m, n, o and p are independently of each other 1 or
 2. 30. Thecompound as claimed in claim 29, where m and n are both 1 or are both 2.31. The compound as claimed in claim 29, where o and p are both 1 or areboth
 2. 32. A compound selected from the group consisting of:N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(3-morpholinopropyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(3-morpholinopropyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(3-morpholinopropyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-fluoro-4-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-fluoro-4-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-fluoro-4-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-diethylaminoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-diethylaminoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-diethylaminoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-1-(4-methoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-1-(4-methoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-1-(4-methoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[2-(1-piperidyl)ethyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[2-(1-piperidyl)ethyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[2-(1-piperidyl)ethyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-fluoro-4-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-fluoro-4-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-fluoro-4-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-6-fluoro-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-6-fluoro-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-6-fluoro-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;3-(2-Ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-3-[2-[2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptan-6-yl]-2-oxo-ethyl]-2-oxo-indoline-5-carbonitrile;(3S)-3-(2-Ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-3-[2-[2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptan-6-yl]-2-oxo-ethyl]-2-oxo-indoline-5-carbonitrile;(3R)-3-(2-Ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-3-[2-[2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptan-6-yl]-2-oxo-ethyl]-2-oxo-indoline-5-carbonitrile;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethoxy)-6-azaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethoxy)-6-azaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethoxy)-6-azaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;(3S)-N-[5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;(3R)-N-[5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;(3S)-N-[5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;(3R)-N-[5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(2-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[1-(Benzenesulfonyl)-5-cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-1-(Benzenesulfonyl)-5-cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-1-(Benzenesulfonyl)-5-cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxyphenyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxyphenyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxyphenyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxyphenyl)-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxyphenyl)-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxyphenyl)-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxyphenyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxyphenyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxyphenyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxyphenyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxyphenyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxyphenyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-[1-(oxetan-3-yl)-4-piperidyl]-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxyphenyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxyphenyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxyphenyl)-2-oxo-indolin-3-yl]-2-(1-methyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxyphenyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxyphenyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxyphenyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxyphenyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxyphenyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxyphenyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxyphenyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxyphenyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-1-(4-cyanophenyl)sulfonyl-3-(2-ethoxyphenyl)-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxyphenyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxyphenyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxyphenyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(1-isopropyl-4-piperidyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-azaspiro[3.3]heptane-2-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-azaspiro[3.3]heptane-2-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-azaspiro[3.3]heptane-2-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-(1-isopropyl-4-piperidyl)-6-azaspiro[3.3]heptane-2-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-(1-isopropyl-4-piperidyl)-6-azaspiro[3.3]heptane-2-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-(1-isopropyl-4-piperidyl)-6-azaspiro[3.3]heptane-2-carboxamide;N-[5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-(1-methylazetidin-3-yl)-6-azaspiro[3.3]heptane-2-carboxamide;N-[(3S)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-(1-methylazetidin-3-yl)-6-azaspiro[3.3]heptane-2-carboxamide;N-[(3R)-5-Cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-6-(1-methylazetidin-3-yl)-6-azaspiro[3.3]heptane-2-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(piperidin-4-yl)-3-azaspiro[5.5]undecane-9-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-3-(piperidin-4-yl)-3-azaspiro[5.5]undecane-9-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-3-(piperidin-4-yl)-3-azaspiro[5.5]undecane-9-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)spiro[3.3]heptane-2-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-6-(2,6-diazaspiro[3.3]heptan-2-yl)spiro[3.3]heptane-2-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-6-(2,6-diazaspiro[3.3]heptan-2-yl)spiro[3.3]heptane-2-carboxamide;N-(5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-7-(piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxamide;N-[(3S)-5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-indolin-3-yl]-7-(piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxamide;N-[(3R)-5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-indolin-3-yl]-7-(piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-2-(piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-2-(piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-2-(piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-2,7-diazaspiro[3.5]nonane-7-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-2,7-diazaspiro[3.5]nonane-7-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-2,7-diazaspiro[3.5]nonane-7-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-azaspiro[5.5]undecane-9-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-3-azaspiro[5.5]undecane-9-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-3-azaspiro[5.5]undecane-9-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-9-methyl-3,9-diazaspiro[5.5]undecane-3-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-9-methyl-3,9-diazaspiro[5.5]undecane-3-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-9-methyl-3,9-diazaspiro[5.5]undecane-3-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(4-ethylpiperazin-1-yl)spiro[3.3]heptane-2-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-6-(4-ethylpiperazin-1-yl)spiro[3.3]heptane-2-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-6-(4-ethylpiperazin-1-yl)spiro[3.3]heptane-2-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-9-ethyl-3,9-diazaspiro[5.5]undecane-3-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-9-ethyl-3,9-diazaspiro[5.5]undecane-3-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-9-ethyl-3,9-diazaspiro[5.5]undecane-3-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-2-azaspiro[3.3]heptane-6-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-2-azaspiro[3.3]heptane-6-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-2,6-diazaspiro[3.3]heptane-2-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-2,6-diazaspiro[3.3]heptane-2-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-6-(piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide;N-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-6-(piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide;N-(5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxamide;N-[(3S)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-2,7-diazaspiro[3.5]nonane-2-carboxamide;andN-[(3R)-5-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl]-2,7-diazaspiro[3.5]nonane-2-carboxamide;or an N-oxide, stereoisomer, and or pharmaceutically acceptable saltthereof, or wherein at least one of the atoms has been replaced by itsstable, non-radioactive isotope.
 33. A pharmaceutical compositioncomprising at least one compound of the formula I as defined in claim 1and/or an N-oxide, a stereoisomer or at least one pharmaceuticallyacceptable salt thereof and at least one pharmaceutically acceptablecarrier.
 34. A method for the treatment of vasopressin-related diseasescomprising administering a compound of claim 1, or an N-oxide, asteroisomer or pharmaceutically acceptable salt thereof, to a subject inneed thereof.
 35. The method as claimed in claim 34, wherein thevasopressin-related diseases are selected from the group consisting ofdiabetes; insulin resistance; nocturnal enuresis; incontinence anddiseases in which impairments of blood clotting occur; hypertension;pulmonary hypertension; heart failure; myocardial infarction; coronaryspasm; unstable angina; PTCA (percutaneous transluminal coronaryangioplasty); ischemias of the heart; impairments of the renal system;edemas; renal vasospasm; necrosis of the renal cortex; hyponatremia;hypokalemia; Schwartz-Bartter syndrome; impairments of thegastrointestinal tract; gastritic vasospasm; hepatocirrhosis; gastricand intestinal ulcers; emesis; emesis occurring during chemotherapy;travel sickness; affective disorders; Alzheimer's disease; mildcognitive impairment and cognitive impairment associated withschizophrenia, aging, Alzheimer disease, Parkinson's disease and/ordementia; increased aggression in conditions selected from the groupconsisting of Alzheimer's disease, schizophrenia, bipolar disorder,frontal lobe injuries and substance use disorders; Cushing's syndromeand stress-dependent diseases; sleep disorders; vasomotor symptoms;thermoregulatory dysfunctions; substance-related and addictivedisorders; schizophrenia and psychosis; pain; and micturition disorders.36. The method as claimed in claim 35, where the affective disorders areselected from the group consisting of depressive disorders, anxietydisorders and stress-dependent anxiety disorders; where thesubstance-related and addictive disorders are selected from the groupconsisting of alcohol use disorder, alcohol intoxication, and alcoholwithdrawal.
 37. The method as claimed in claim 35, where the affectivedisorders are selected from the group consisting of depressivedisorders, anxiety disorders, obsessive-compulsive disorders, trauma andstressor-related disorders; and bipolar disorders; wheresubstance-related and addictive disorders are selected from the groupconsisting of substance use disorder, substance-induced disorder,alcohol use disorder, alcohol intoxication, alcohol withdrawal, caffeineintoxication, caffeine withdrawal, cannabis use disorder, cannabiswithdrawal, phencyclidine use disorder, other hallucinogen usedisorders, phencyclidine intoxication, other hallucinogen disorders,hallucinogen persisting perception disorder, inhalant use disorder,inhalant intoxication, opioid use disorder, opioid withdrawal, sedative,hypnotic or anxiolytic use disorder, sedative, hypnotic or anxiolyticwithdrawal, stimulant use disorder, stimulant intoxication, stimulantwithdrawal, tobacco use disorder, tobacco withdrawal, and gamblingdisorder.
 38. The method as claimed in claim 37, where the depressivedisorders are selected from the group consisting of dysthymic disorders,major depression, seasonal depression, treatment-resistant depressiondisorders, disruptive mood dysregulation disorder, premenstrualdysphoric disorder, substance/medication-induced depressive disorder andchildhood onset mood disorders; where the anxiety disorders are selectedfrom the group consisting of phobias, specific phobias, general anxietydisorders, panic disorders, drug withdrawal-induced anxiety disorders,separation anxiety disorder, selective mutism, social anxiety disorder,agoraphobia, and substance/medication-induced anxiety disorder; theobsessive-compulsive are selected from the group consisting ofobsessive-compulsive disorder, body dysmorphic disorder, hoardingdisorder, trichotillomania, excoriation disorder, andsubstance/medication-induced obsessive-compulsive disorder; the traumaand stressor-related disorders are selected from the group consisting ofreactive attachment disorder, disinhibited social engagement disorder,post-traumatic stress disorder, acute stress disorder, ad adjustmentdisorder; and the bipolar disorders are selected from the groupconsisting of bipolar I disorder, bipolar II disorder, cyclothymicdisorder, and substance/medication-induced bipolar disorder.